IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION: PROGNOSTIC FACTORS AND CLINICAL PRESENTATION

ИДИОПАТИЧЕСКАЯ ЛЕГОЧНАЯ АРТЕРИАЛЬНАЯ ГИПЕРТЕНЗИЯ: ПРОГНОСТИЧЕСКИЕ ФАКТОРЫ И КЛИНИЧЕСКАЯ КАРТИНА

Йео Мухаммад Аль-Хабиб

студент, институт мировой медицины, Российский Национальный Исследовательский Медицинский Университет,

РФ, г. Москва

Журавлёв Александр Константинович

научный руководитель, д-р мед. наук, проф. кафедры пропедевтика внутренних болезней лечебного факультета Российский Национальный Исследовательский Медицинский Университет,

РФ, г. Москва

ABSTRACT

Idiopathic pulmonary artery hypertension (IPAH) is a progressive disease characterized by remodeling and occlusion of the pulmonary vasculature, leading to consistently elevated mean pulmonary artery pressure (mPAP) and increased pulmonary vascular resistance (PVR). The disease's pathophysiology is marked by severe arteriopathy, including vascular lesions like plexiform lesions, which are unique to IPAH. This review explores the clinical characteristics, diagnostic challenges, and prognostic factors associated with IPAH. Key prognostic predictors such as the World Health Organization functional class (WHO-FC), the 6-minute walk distance (6MWD), and biomarkers like BNP/NT-proBNP are discussed. The paper highlights the current clinical classification and risk stratification methods, including the ESC/ERS guidelines, and addresses the need for further research on phenotypic subgroups that may impact diagnosis and treatment.

АННОТАЦИЯ

Идиопатическая легочная артериальная гипертензия (ИЛАГ) — прогрессирующее заболевание, характеризующееся ремоделированием и окклюзией легочных сосудов, что приводит к постоянному повышению среднего давления в легочной артерии (сДЛА) и увеличению легочного сосудистого сопротивления (ЛСС). Патофизиология заболевания включает тяжелую артериопатию, в том числе сосудистые поражения, такие как плексформные поражения, уникальные для ИЛАГ. Этот обзор рассматривает клинические особенности, диагностические трудности и прогностические факторы, связанные с ИЛАГ. В статье обсуждаются ключевые прогностические предсказатели, такие как функциональный класс Всемирной организации здравоохранения (ВОЗ-ФК), шестиминутный тест ходьбы (T6МХ) и биомаркеры, такие как BNP/NT-proBNP. Рассматривается текущая клиническая классификация и методы оценки риска, включая рекомендации ESC/ERS, а также подчеркивается необходимость дальнейших исследований фенотипических подгрупп, которые могут повлиять на диагностику и лечение.

Keywords: Idiopathic pulmonary artery hypertension, IPAH, pulmonary hypertension, 6MWD, NT-proBNP, WHO-FC.

Ключевые слова: Идиопатическая легочная артериальная гипертензия, ИЛАГ, легочная гипертензия, Т6МХ, ФК-ВОЗ.

INTRODUCTION

Idiopathic pulmonary artery hypertension (IPAH) is a progressive disease affecting the precapillary pulmonary vasculature. It is marked by remodeling and occlusion of the pulmonary vasculature, resulting in a consistently elevated mean pulmonary artery pressure (mPAP) exceeding 25 mmHg at rest and greater than 30 mmHg during physical activity, a pulmonary artery wedge pressure (PAWP) of <15 mmHg and a PVR >2 WU [1, 2, 3, 4].

The current clinical classification of pulmonary hypertension consists of five major groups [1, 5]:

Group 1: Pulmonary arterial hypertension (PAH)

Group 2: Pulmonary hypertension related to left heart disease

Group 3: Pulmonary hypertension related to hypoxia or lung disease

Group 4: Chronic thromboembolic pulmonary hypertension

Group 5: Pulmonary hypertension due to systemic or miscellaneous multifactorial conditions

The Dana Point Clinical Classification further divides PAH (Group 1) into idiopathic, heritable, drug and toxin induced, PAH associated with other conditions (connective tissue diseases, HIV infection, congenital heart disease, portal hypertension, schistosomiasis, chronic hemolytic anemia) and persistent PH of the newborn [6]. The etiology of IPAH remains largely unknown, although familial cases have been identified, suggesting a potential genetic component involving mutations that increase vascular susceptibility to vasoconstrictors, alongside environmental influences [1]. IPAH is associated with severe arteriopathy characterized by thickening of peripheral arterial layers and muscularization of precapillary arterioles and capillaries. These changes lead to the formation of vascular lesions (plexiform lesions and neointimal proliferation) which can obstruct pulmonary blood vessels and increase pulmonary artery resistance. Plexiform lesions are unique to IPAH and result from monoclonal proliferations of endothelial cells, smooth muscle cell migration and proliferation, and accumulation of inflammatory cells. These lesions are unique to IPAH and are not commonly seen in other diseases [7, 8, 9]. As the disease advances, the continuous rise in pressure exacerbates pulmonary hypertension, eventually causing right ventricular hypertrophy and possibly heart failure if left untreated [10]. This review paper will primarily focus on the prognostic risk factors associated with Idiopathic Pulmonary Arterial Hypertension (IPAH) and explore the underlying pathophysiological mechanisms involved.

METHODS AND MATERIALS

Literature for this review was obtained from PubMed and Google Scholar directory using the different keywords like “IPAH”, “idiopathic pulmonary arterial hypertension”, “6MWD”, “WHO-FC”, “NT-proBNP and others.

DISCUSSION

PATIENT PRESENTATION AND DIAGNOSTIC METHODS

Idiopathic pulmonary arterial hypertension (IPAH), a significant subtype of PAH manifests as non-specific clinical symptoms that predominantly reflect progressive right heart dysfunction. Patients often experience fatigue, dyspnea, chest tightness, chest pain, and syncope [11]. Among these, exertional dyspnea stands out as the most prevalent symptom of pulmonary hypertension (PH), frequently accompanied by additional symptoms such as near-syncope, palpitations, chest discomfort, and peripheral edema as the condition advances. During physical examinations, signs of right heart failure may become evident, including jugular venous distention, an accentuated second heart sound, a right-sided fourth heart sound and tricuspid regurgitation murmur. In the early stages of the disease, symptoms typically arise during exertion but tend to worsen with minimal activity over time [1]. Physicians may suspect pulmonary arterial hypertension (PAH) based on clinical presentation, but diagnosing idiopathic pulmonary arterial hypertension (IPAH) is challenging due to nonspecific symptoms that overlap with various cardiac and pulmonary disorders, making it crucial to exclude other potential causes of pulmonary hypertension [1]. Echocardiography serves as the most sensitive initial test for assessing the right ventricular size and estimating pulmonary artery pressure, while pulmonary function tests typically reveal impaired diffusion capacity (DLCO) [1].

Right heart catheterization, the gold standard for accurate pressure measurement, shows elevated mean pulmonary artery pressures with normal pulmonary capillary wedge pressure in IPAH patients. Vasoreactivity testing during catheterization is essential to identify acute responders who may benefit from high-dose calcium channel blockers [1, 3]. Acute responders are identified by a decrease in the mean pulmonary artery pressure (mPAP) by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output [1, 3].

PROGNOSTIC PREDICTORS

With regards to prognostic predictors, three parameters, namely the WHO-FC, 6MWD, and BNP/NT-proBNP levels are often utilized to assess the risk group and disease severity of patients with IPAH in accordance with ESC/ERS guidelines. The World Health Organization Functional Class (WHO-FC) acts as a reliable predictor of survival at the time of diagnosis and during follow-up, factoring in limitations in physical activity and related symptoms. A decline in WHO-FC is regarded as one of the most concerning indicators of disease progression [12]. The 6-Minute Walk Distance (6MWD) is also frequently adopted to determine functional exercise capacity, assess treatment efficacy, and predict patient prognosis [13]. A cohort study conducted on 109 patients with IPAH that suggested that a low 6MWD of less than 322 meters was an independent predictor of mortality [14]. Lastly, B-type natriuretic peptide (BNP) and its N-terminal prohormone (NT-proBNP) are the only biomarkers routinely employed in pulmonary hypertension (PH) centers. These biomarkers correlate with myocardial stress and offer prognostic information, although they lack specificity for PH and may also be elevated in other cardiovascular conditions [3, 15]. Notably, IPAH patients with an NT-proBNP level of ≥1,400 pg/ml predicted a fatal outcome within three years of diagnosis [16]. A higher NT-proBNP level was also found to be associated with a poorer WHO-FC [17].

According to the ESC/ERS Guidelines, the three-strata model is recommended for diagnosing patients by evaluating parameters such as WHO functional class (WHO-FC), six-minute walk distance (6MWD), and biomarkers like BNP or NT-proBNP, alongside additional factors including patient presentation, hemodynamics, and right heart imaging findings. Patients were categorized into three risk groups based on their estimated one-year mortality: low risk (5%), intermediate risk (5-20%), and high risk (greater than 20%). Notably, 60-70% of patients are often classified as intermediate risk, highlighting the need for improved discrimination within this group [3]. To address this, a simplified four-strata model has been introduced for patient follow-up, which incorporates WHO-FC, 6MWD, and BNP or NT-proBNP. This model enhances sensitivity to changes in risk by further subdividing the intermediate-risk group into intermediate-low and intermediate-high categories. Several studies have identified these parameters as the most robust prognostic predictors, leading to a more accurate assessment of mortality risk [3, 18, 19].

A recent study that was conducted using the COMPARE and ASPIRE registries proposed adding a phenotypic component to the classification of unexplained pre-capillary pulmonary hypertension, factoring in smoking history, DLCO, chest CT findings, and left heart disease risk factors [20]. It identified a subtype of IPAH patients with a lung phenotype, characterized by a smoking history and low DLCO (45%), who closely resemble those with group 3 pulmonary hypertension (COPD and interstitial lung disease). Both groups consisted of older patients with a male predominance, along with similar WHO-FC, 6MWD, and treatment responses. In contrast, patients with the lung phenotype had few similarities to classical IPAH (young, healthy, predominantly females, absence of pre-defined risk factors for cardiopulmonary disease), apart from severe pre-capillary pulmonary hypertension, complicating diagnosis. The authors highlighted the need for revised diagnostic criteria and further investigation into smoking-related pulmonary vasculopathy [20]. This could also be related to smoking-related interstitial fibrosis as noted by a case study after examining lung histology from a patient with a lung phenotype [21].

CONCLUSION

Idiopathic pulmonary arterial hypertension (IPAH) remains a challenging condition due to its complex pathophysiology and nonspecific symptoms. Early diagnosis is crucial, as the disease progresses rapidly and can lead to right heart failure if untreated. Current prognostic models, which include WHO-FC, 6MWD, and biomarkers like BNP/NT-proBNP, provide valuable tools for risk stratification and help guide therapeutic decisions. However, significant gaps remain in the accurate classification of IPAH, particularly with the emergence of phenotypic subgroups that complicate diagnosis and treatment. Further research into these subgroups, as well as the development of more refined diagnostic criteria, is essential to improving patient outcomes. The evolving understanding of IPAH will pave the way for more targeted therapies and better management strategies.

CONFLICT OF INTEREST

The authors declare the absence of potential conflicts of interest related to the publication of this article.

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