Pulmonary Hypertension, an Evolutional Disease with Multidisciplinary Team Management

Abbreviations

ASIG, Australian Scleroderma Interest Group

BPA, Balloon pulmonary angioplasty

CTD, Connective tissue disease

CTEPH, Chronic thromboembolic pulmonary hypertension

ECG, Electrocardiography

ERS, European Respiratory Society

ESC, European Society of Cardiology

PAH, Pulmonary artery hypertension

PAP, Pulmonary artery pressure

PEA, Pulmonary endarterectomy

PH, Pulmonary hypertension

PVR, Pulmonary vascular resistance

SLE, Systemic lupus erythematosus

SSc, Systemic sclerosis

TACVPR, Taiwan Academy of Cardiovascular and Pulmonary Rehabilitation

TCR, Taiwan College of Rheumatology

TSOC, Taiwan Society of Cardiology

WHO, World Health Organization

WU, Wood units

Pulmonary hypertension (PH) is simply defined as an elevated mean pulmonary artery pressure; however, it is a complex disorder that involves multiple clinical conditions including thromboembolism, cardiovascular, respiratory and systemic diseases. The diagnosis and management of PH requires a multidisciplinary approach with the cooperation of experts in different fields. In 2014, the Taiwan Society of Cardiology (TSOC) published the first guidelines for the diagnosis and management of PH,¹ and the guidelines were subsequently updated with new scientific data in 2019.² The guidelines emphasize detecting possible PH patients in Taiwan according to symptoms/signs, chest X ray, electrocardiography (ECG), and most importantly the early use of echocardiography. Suspected cases should be referred to expert centers for further examinations, and right heart catheterization remains the standard diagnostic tool for PH. Based on these examinations, the etiology of PH can be differentiated into five groups according to the World Health Organization (WHO) classification, and individual management should be applied accordingly. Proper general and special pharmacologic therapy should start early to keep patients at a low-risk status. Regular risk assessment while making the diagnosis and during follow-up is highly recommended for timely treatment escalation to stop disease progression as early as possible. Both the REVEAL 2.0 risk score and European guidelines-based risk assessment scores are recommended for the initial treatment assessment, and European guidelines-based risk assessment scores are mostly used for regular 2~3-month follow-up assessments.³ Lung transplantation remains the last solution for high-risk patients. Educational programs have been promoted for both patients and medical practitioners to establish a referral and supportive care system. Through this system and advances in technology such as telemedicine, most PH patients were kept safe during the COVID-19 pandemic.⁴ The overall survival rate of PH has greatly improved over the last decades. In a report from a single medical center, the 1-, 2-, 3-, and 5-year survival rates were 93%, 88%, 84%, and 77%, respectively in group 1 pulmonary artery hypertension (PAH) patients.⁵ The outcomes of patients with group 4 chronic thromboembolic pulmonary hypertension (CTEPH) have also improved through a multidisciplinary approach to treatment in Taiwan. Compared to Western countries, CTEPH patients in Taiwan receive less pulmonary endarterectomy (PEA), and most are treated with medication, balloon pulmonary angioplasty (BPA), or both. BPA for CTEPH was introduced in the early 2010s in Taiwan, with reported improvements in six-minute walk test, pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and N-terminal pro B-type natriuretic peptide.⁶ Experience with the procedure has led to a decrease in complications and better outcomes, and the ability to perform multi-vessel procedures. Riociguat therapy has also improved these parameters.⁷ Nevertheless, PEA is still associated with the highest cure rate for CTEPH. In Taiwan, it is mostly performed in proximal disease (Jamieson type 1 or 2), with significant reported improvements in symptoms, functional capacity, and hemodynamics.⁸ Considering the emerging role of combination therapy in PAH, most CTEPH patients receive combination therapy with medications, PEA or BPA for better symptom control in Taiwan, especially for patients with a high mean PAP (≥ 20 mmHg) after PEA or BPA.

Beyond this progress, new evidence and developments continue to improve treatment and outcomes. Along with improvements in therapy awareness of the disease, PH patients are becoming older, and have more comorbidities and atypical presentations.⁹ In 2022, the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) published new guidelines for the diagnosis and treatment of PH.¹⁰ Different from the previous PH guidelines in 2015,¹¹ the new guidelines recommended new definitions of PH, including a mean PAP down from 25 to 20 mmHg, and PVR down from 3 to 2 Wood units (WU). In addition, the definition of exercise PH was added. The new definitions emphasize the need to start treating the underlying disease as early as possible in group 2 and 3 patients. Although the efficacy of specific therapy in group 1 and 4 patients with a mean PAP 21-24 mmHg and/or PVR 2-3 WU is still unknown, close follow-up of these patients can prompt treatment of these patients at an early stage. Based on current evidence, early combination therapy is suggested for low-risk WHO functional class II patients, because PAH rapidly deteriorates even in patients with less advanced disease.¹² The PAH treatment algorithm was modified in the 2022 ESC guidelines, highlighting the importance of risk assessment both while making the diagnosis and during follow-up, and the importance of initial combination therapy. A three-strata multi-parametric model is recommended to guide treatment decisions at diagnosis, and a four-strata risk assessment is recommended during follow-up. In addition, some parameters for risk stratification have been adjusted, and new imaging modalities such as cardiac magnetic resonance imaging have been added. Initial combination therapy is favored except for patients with cardiopulmonary comorbidities. The treatment goal is to keep the patients at a low-risk status, and up-titration of therapy is needed if the patients do not meet the treatment goal. In Taiwan, the National Health Insurance program does not cover initial PAH-specific combination therapy for low-risk groups, however early combination therapy can be used if the patient does not achieve the treatment goal. The use of imaging modalities such as cardiac magnetic resonance imaging and nuclear imaging¹³ can be applied to help evaluate disease severity and guide therapy. Apart from pharmacological therapy, cardiopulmonary exercise test and rehabilitation have been shown to improve the quality of life.^14,15 The TSOC and Taiwan Academy of Cardiovascular and Pulmonary Rehabilitation (TACVPR) promote a rehabilitation program for PAH patients, including walking, using a bicycle ergometer, resistance training with low weights, and respiratory exercise.¹⁶ In addition to these measures, some translational studies using gene analysis and mir-21 have been conducted in Taiwan,¹⁷ and one study of a Taiwanese idiopathic and heritable PAH cohort identified that 17.8% of the patients had BMPR2 gene variants and 17.8% had other 6th WSPH-listed PAH-related gene variants.¹⁸ The study also reported that the PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having a higher mean PAP at the initial diagnosis, emphasizing the need to screen for PH in their relatives. In addition, a novel BMPR2 variant gene was identified in a patient with hereditary PAH combined with pulmonary arteriovenous malformations.¹⁹ The expression of systemic and pulmonary miR-21 has also been associated with the severity of right ventricular dysfunction in patients with hypoxia-induced PH.²⁰ These findings may suggest that miR-2 could be a novel biomarker, which could be used to identify novel pathologic changes and new therapeutic targets for this disease. Other novel therapies for PAH in both experimental and pre-clinical phase 1 and 2 trials involving mitochondrial dysfunction, immune and inflammatory pathways, gene mutations, DNA damage, epigenetic modification, stem cell therapy, and pulmonary artery denervation are also currently under investigation.²¹ However, there is still a large gap between these preliminary data and clinical practice.

Of all subgroups of group 1 PAH, patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) have the poorest outcomes. In a Taiwan national cohort study, 7.68% of patients with systemic sclerosis (SSc) and 2.06% of those with systemic lupus erythematosus (SLE) developed PAH. Different from western countries where up to 60% CTD-PAH patients are SSc, the prevalence of SLE is higher than SSc in Taiwan, and the most common CTD among all CTD-PAH patients is SLE (57%), followed by SSc (30%).²² The 1-, 3- and 5-year survival rates for SSc-PAH have been reported to be 88.3%, 72.1% and 61.9%, respectively, compared to 87.6%, 75.8% and 69.4% for SLE-PAH.²² Another cohort study reported 1-, 3- and 5-year survival rates of 87.7%, 76.8% and 70.1%, respectively, in SLE-PAH patients in Taiwan.²³ The key to survival relies on early detection, early effective management of both CTD/PAH, and multidisciplinary team management. The TSOC and Taiwan College of Rheumatology (TCR) together published the Taiwan Connective Tissue Disease Pulmonary Arterial Hypertension Consensus based on the disease characteristics in Taiwan.²⁴ Taiwanese patients with SSc are at a higher risk of PAH than those with SLE, however most CTD-PAH patients in Taiwan have SLE. The Western screening protocol mainly focused on SSc, and so it does not fit the situation in Taiwan. Therefore, we recommend a different screening strategy for SSc and non-SSc CTD patients. For SSs patients, we recommend the DETECT or Australian Scleroderma Interest Group (ASIG) algorithm to detect high-risk cases, similar to other international guidelines. For non-SSc patients, we recommend identifying high-risk cases by clinical presentation, serological biomarkers, and ECG. In high-risk groups, we suggest checking for the possibility of PH using echocardiography first, and then following the diagnostic algorithms in the TSOC PH guidelines. Similar to the 2022 ESC/ERS PH guidelines, four-strata risk stratification is suggested to evaluate the disease risk. The definition of PH is also a mean PAP > 20 mmHg and PVR > 2 WU. CTD is a systemic disease, and CTD-PH is caused not only by group 1 PAH but also other forms of PH. CTD patients often have overlapping forms of PH, and PAH-specific medications should only be given when PAH is involved. PAH-specific treatment should be initiated when the patients’ mean PAP is ≥ 25 mmHg and PVR ≥ 3 WU according to the results of recent clinical trials. Combination therapy, and not only combination therapy for PAH but also specific combination therapy for CTD and PAH, is emphasized. For high-risk patients, non-parenteral prostanoids should be used initially. Early and effective detection and treatment are the key points in this consensus. We hope that the guidelines and consensus will encourage the use of a cooperative multidisciplinary approach for this complex disease, and thereby improve the prognosis and quality of life of the patients.

DECLARATION OF CONFLICT OF INTEREST

The authors declare no conflict of interest.