Pulmonary Hypertension: Revisiting the Historical Facts

Abstract

Pulmonary hypertension is a progressive and potentially fatal medical condition. Around 1% of global population is estimated to be affected by it. With significant advancement in diagnostic and therapeutic modalities in pulmonary hypertension, there has been a surge in interest in medical fraternity. We aim to revisit some of the major historical events pertinent to the evolution of the field of pulmonary hypertension. We try to understand how our predecessors in medicine laid foundation based on which the field of pulmonary hypertension is growing.

1. Introduction

Pulmonary hypertension (PH) is an uncommon, progressive, and potentially life-threatening medical condition that is basically characterized by elevated blood pressure in the pulmonary arteries [1, 2]. The pulmonary arteries are blood vessels that carry oxygen-poor blood from the right side of the heart to the lungs to get oxygenated. Around 1% of the global population is estimated to be affected by pulmonary hypertension [3]. It is more frequently observed in women between the ages of 30 and 60, and Hispanic women and African American women are disproportionately impacted [1, 2]. However, PH can affect people of all ages, and incidence increases with age. There has been advancement in diagnostic and therapeutic modalities in PH in the past decade or so. There seems to be a simultaneous increase in interest and awareness about PH in the medical fraternity as well. PH is an evolving field in medicine. In this chapter, we will be revisiting the historical perspectives and reviewing the major events that have unfolded in the course of understanding this unique disease entity.

2. Early observations and recognition in PH

The earliest known description of PH dates to 1891. A German Physician, Ernst Von Romberg, was presented with a 24-year-old patient suffering from shortness of breath, tiredness, and cyanosis. Unfortunately, he was unable to treat the young man, who subsequently passed away. During his autopsy, Dr. Romberg noted thickened and damaged pulmonary arteries; to define this previously unidentified condition, he coined the term “Pulmonary Hypertension.” Since no tool to measure the pressure in the pulmonary vascular system had been invented yet, the only reliable evidence indicative of elevated pulmonary artery pressure was the presence of cardiac and vascular remodeling during autopsy [4, 5].

Further development in PH followed a decade later. In August 1901, an Argentinian Professor, Dr. Abel Ayerza, expanded the definition of pulmonary hypertension. Dr. Ayerza’s patient was a 38-year-old male with polycythemia presenting with a chronic productive cough, dyspnea, cyanosis, and daytime somnolence. His examination revealed crackles and acute wheezing bilaterally in addition to jugular venous distention, hepatomegaly, ascites, and lower limb edema. Laboratory tests depicted an elevated systolic blood pressure of 150 mmHg with a heart rate of 112 bpm [6]. Twenty-four days following admission, this patient also expired. His autopsy revealed right ventricular hypertrophy and right atrial dilation. The pulmonary arteries had thickened media and intimal layers with the presence of microthrombi in the lumen. Dr. Ayerza termed this unique set of symptoms as “Cardiaco Negros (black cardiac)” [7].

Four years later, Dr. Pedro Escudero reported new findings that further deepened the understanding of this condition. He recorded the presence of black cardiac disease in patients with bronchial syphilis [8]. His paper indicated that the disease was a result of syphilis damaging the pulmonary vessels rather than due to pulmonary disease. His work was rapidly followed up on by Dr. F.C Arigilla in 1913, a pupil of Ayerza’s. He carried out a case series on 11 patients [9]. His research grouped all those patients with the common symptoms of cyanosis, dyspnea, and polycythemia. “Ayerza’s disease” was a term that had begun to be used to describe patients with pulmonary vascular sclerosis presenting with these symptoms [7]. However, Dr. Arigilla’s work was novel in noting that these common symptoms were not specific and, in fact, presented various etiologies. Prior to this finding, the absence of any signs of pulmonary disease in patients with such symptoms was puzzling to physicians.

In 1919, the confusion and misconceptions around “Ayerza’s” disease seemed to have further been resolved when Dr. Aldred Warthin first discussed the case in the United States at the 34th Meeting of the American Society of Medicine [10]. He presented a patient with the standard clinical presentation of cyanosis, dyspnea, and fatigue, with autopsy results yielding evidence of syphilitic disease. This aligned with Dr. Escudero’s and Dr. Arigilla’s reports of syphilitic patients as well. Hence, at the time, the consensus was made that this presentation of “Ayerzas Disease” was an outcome of syphilis [6].

The aforementioned theory was challenged in 1935 by Dr. Oscar Brenner. He had studied 100 patients, all with the same symptoms of cyanosis, dyspnea, and fatigue. However, he found that not many of the patients had the same severity of symptoms that were described by Dr. Argilla. Moreover, Dr. Brenner found evidence of pulmonary vascular sclerosis (as described by Dr. Romberg) in patients with no evidence of syphilis [11]. Dr. Brenner himself could not explain the cause of the vascular remodeling in some of his patients. Hence, he concluded that there were a variety of causes of pulmonary hypertension, some of which could not be explained at the time. His work also suggested that the symptoms of Ayerza’s disease were not, in fact, a disease but rather an outcome of the pulmonary remodeling, which he hypothesized was due to pulmonary arterial hypertension. This theory was pivotal in shaping how we describe this condition today [7].

Dr. Brenner’s publication was widely recognized among the medical community. Pulmonary hypertension became the official term to describe this condition. Multiple reports in the 1940s, including those published in Guy’s Hospital and Kings College London, described patients whose presentations matched Dr. Brenner’s proposed definition of pulmonary hypertension [12]. Trials carried out at Kings College London reported an enlarged right ventricle and a dilated pulmonary artery in their autopsy reports, which aligned with their X-ray and electrocardiogram (ECG) findings as well [12]. Another interesting finding worth noting was the “Hilar Dance” phenomenon, which refers to the pulsating motion of the pulmonary artery, possibly due to the increased blood flow and pressure in these vessels. This was the first time imaging techniques had been used on patients with PH and would go on to inspire the basis of future imaging techniques [7].

3. Historical perspectives of chronic thromboembolic pulmonary hypertension (CTEPH)

Chronic Thromboembolic Pulmonary Hypertension (CTPH) is an infrequently encountered outcome of pulmonary embolism that was first discussed in the 1950s [13]. The pathogenesis involves multiple pulmonary embolisms lodging in the pulmonary vasculature. Over time, the occlusion of circulation leads to the development of cor pulmonale and eventually right-sided heart failure. However, what makes this condition unique and often hard to identify is the silent asymptomatic period, which occurs after the thrombus lodges in the vasculature. Simultaneously, cardiac remodeling silently occurs in the background.

Following its identification, initial surgical management was tested in the early 1960s, however, with little success. Due to the rarity of this disorder and the lack of existing knowledge about it, surgical outcomes were poor. It was not until 1969 when Ken Moser at the University of California in San Diego developed a new procedure known as the thromboendarterectomy, that the outcomes of this radically improved [14]. After initially carrying out the procedure on a single patient in 1970, Dr. Moser published his breakthrough findings in 1983, when he had successfully managed to improve outcomes in 13 out of the 15 patients through the thromboendarterectomy procedure [14]. By 2002, due to a wide variety of factors, the mortality rate of CTPH had been reduced to 4.4%, with major improvements in patient performance. The development of new diagnostic and imaging tests has led to earlier diagnosis and initiation of treatment for patients with CTPH [14]. Moreover, improvements in surgical techniques and increased experience among doctors have improved patient outcomes. This procedure created by Dr. Ken Moser has saved numerous lives and proved to be an undeniable success in the field of pulmonary surgery [15].

4. Evolution of right heart catheterization in pulmonary hypertension

Cardiac catheterization was first attempted in Germany in 1929 by Dr. Wener Frossman. In his quest to introduce a safe method of studying cardiac and pulmonary hemodynamics, he inserted a urinary catheter into his own heart [16]. While this experiment was somewhat successful, it was deemed dangerous by the medical community, and Forssman was exiled due to his unsafe practice in medicine. However, his work would not go unnoticed. This quickly caught the attention of André Cournand and Dickinson Richards in the United States of America. They realized how mixed venous blood samples from the catheter would allow the cardiac output to be calculated using the Ficks Equation—a calculation that had previously only been explored theoretically since there was no way to access these blood samples [17].

In 1945, the duo carried out cardiac catheterization more than 250 times, each time with no significant complications to the patients. They also managed to use the catheters to collect the mixed venous samples and calculate the cardiac output using the Ficks Principle. Their work led them, along with Dr. Frossman, to win the Nobel Prize. Right heart catheterization (RHC) paved the way for further research into PH [16, 17].

5. World Health Organization (WHO) Geneva meeting 1973: an important milestone

In November of 1965, Aminorex Fumarate was released into markets in parts of Europe and advertised as an ordinary over-the-counter appetite suppressant helping in weight loss. Its mode of action was increasing the levels of 5-hydroxytryptamine (serotonin) in the bloodstream and releasing norepinephrine from neurons [18]. However, the drug came with an unexpected and fatal side effect in a small portion of the population, leading to a more than a twenty-fold increase in global Primary PH occurrence [19]. This inevitably led to its removal from markets in October 1968.

There were many questions raised regarding the mechanism of how Aminorex caused PPH. However, the most popular theory suggests that the elevated serotonin levels caused the proliferation of the pulmonary arterial smooth muscle, causing pre-capillary PH. Interestingly, studies conducted by Kay et al. found that when given to animals, Aminorex did not lead to PH development [20]. This raised another question regarding what led to animals, as well as the majority of Aminorex users, not developing any disease. Was there a chance of genetic predisposition in the populations that developed PH? Due to the disease’s rarity, there was also limited information available regarding the different etiologies and their causative mechanisms. This led to the WHO calling its first meeting focused solely on pulmonary hypertension.

There were two primary objectives the WHO aimed to address in the meeting in Geneva. The first objective was to create consensus among experts about the true definition of primary pulmonary hypertension. Up until then, the nomenclature regarding PH was rather convoluted, with the same names being given to multiple etiologies of PH. Indeed, at that time, there were two distinct diseases being referred to as primary hypertension: one used by clinicians to define PH due to an unidentifiable cause, and the second one was used by morphologists for a group of histopathological changes in the pulmonary vasculature, which were closely related to pulmonary arterial hypertension [21]. It was decided to rename these morphological changes to plexogenic pulmonary arteriopathy. Additionally, they concluded that hypoxia, drugs (such as Aminorex), connective tissue disorders, and chronic thromboembolism were all causes of PPH [21].

The second objective of this meeting was to establish an international registry of PH patients. Since the disease was so rare, it would be beneficial to record any updates regarding the disease’s etiology, patient outcomes, and treatments that could potentially lead to the establishment of a standardized protocol of care for patients with PH [21]. Notably, the criteria for diagnosis of PH were also defined at this meeting. Since histopathological and clinical signs may differ, the gold standard of diagnosis of PH was defined as a pulmonary arterial pressure of ≥25 mmHg as measured by cardiac catheterization [21].

Despite the WHO’s suggestions, an international registry for PH patients was never established [22]. Instead, the National Institutes of Health’s (NIH) Heart Lung and Blood Institute launched its own registry, which managed to collect data for 6 years between 1981 and 1987. There were multiple wings established by the NIH, which aimed to collect a wide variety of patient data and help spread knowledge about the clinical presentation and pathophysiology of PH [22].

On the 25th anniversary of their initial meeting in 1998, the WHO met in Evian, France, to discuss developments in PH research. A new classification system known as the “Evian classification” was created to categorize cases of PH into five groups: (1) Pulmonary arterial hypertension (PAH), (2) pulmonary venous hypertension (PVH), (3) PH due to lung disease, (4) chronic thromboembolic PH, and (5) miscellaneous causes [23].

6. Heart lung transplant in pulmonary hypertension

In 1981, a team of three doctors at Stanford University performed the first heart-lung transplant to treat a patient with PAH [24]. Up until then, the survival rates of PH had been marginal, with the average survival duration being 2.8 years. Hence, the work of Dr. Norman Shumway, John Wallwork, and Bruce Reitz was revolutionary in our understanding of the treatment of PAH. In the following years, multiple different surgical procedures were developed based on the first successful heart-lung transplant. The survival post-lung transplant is improving.

7. BMPR gene mutation

Initial evidence of a genetic link to primary pulmonary hypertension was presented in 1997 by Nichols WC et al. When running a genome-wide search for genes in patients with PH, he discovered that families with a high prevalence of PH had changes on the Q arm of chromosome 2 [25]. Then, in 1998, Deng et al. correctly identified that the bone morphogenic protein receptor 2 (BMPR 2) gene had a group of mutations that were strongly associated with PH [26]. Interestingly, the association of the genes with PH also showed sexual dimorphism, with penetrance in females being three times higher (42%) than males (14%) [26, 27]. This was the first time a genetic link had been established for PH and allowed for a way to identify high-risk families.

For the purposes of genetic testing and alterations, animal testing has been employed, particularly in rodents such as rats and mice. Mice are the animal of choice due to the relative ease with which their genetic sequences can be manipulated [28]. Animal testing has allowed us to identify which sets of mutations lead to a worse outcome of PH, as well as the relationship between BMPR mutations and changes in the Tissue Growth Factor Beta (TGF-B) genes [28]. However, the role of TGF-B is incredibly complex and is a gene that requires further research.

8. Conclusion

Revisiting the unfolding of major events in the field of pulmonary hypertension and medicine, in general, helps us understand the contribution of our predecessors in medicine. It awakens a sense of appreciation for their effort and encourages us to utilize that information to form a foundation on which further research and development can be done.