Takayasu arteritis (TA) is a chronic vasculitis of unknown etiology predominantly affecting young females. Besides the aorta and its branches as classic sites of disease, TA may also involve the pulmonary arteries. The vascular inflammation in TA can result in arterial wall thickening, stenosis/occlusion, and aneurysmal dilatation. Diagnosis of pulmonary artery involvement (PAI) can be delayed due to non-specific presenting symptoms. It leads to significant vascular damage at the time of diagnosis and increase in serious cardiopulmonary sequels, particularly pulmonary hypertension (PH). These complications have an adverse impact on the prognosis and risk of invasive intervention.1–3

In recent years, with advances in imaging modalities, PAI in TA patients has been a concerning issue.4 The frequency of the pulmonary arteritis varies greatly among studies and has been reported to range generally between 5.7% and 26% based on the recent studies,2 and up to 56% in autopsy reports.5,6

During the course of Takayasu arteritis, pulmonary hypertension may develop in 0–20% of patients secondary to pulmonary arteritis (PA) (group 4 PH) or left heart disease (group 2 PH).2 Pulmonary hypertension due to pulmonary arteritis is a form of pre-capillary PH characterized by increased vascular resistance; it is hemodynamically distinguished from a PH developed primarily due to left heart disease (LHD) in TA.7 Transthoracic echocardiography (TTE) is a valuable non-invasive tool in detecting early PH signs via measuring cardiac hemodynamic.8 Given the insidious nature of pulmonary artery involvement and subsequent pulmonary hypertension, early diagnosis and intervention before the occurring of irreversible sequels is critical. This study aimed to investigate, the incidence of pulmonary hypertension in Takayasu arteritis patients using the echocardiography findings relating to the functional status of patients.

This study was conducted from January 2016 to December 2019, and the protocol for the research and data collection was approved by the Institutional Ethics Committee.

Takayasu arteritis patients who were being followed at rheumatology outpatient clinics of two general academic hospitals were enrolled. The medical records were reviewed. All patients fulfilled the 1990 criteria of the American College of Rheumatology for the diagnostic classification of Takayasu arteritis.9 The patients with incomplete records, lost follow-up and those with prior known history or risk factors for PH were excluded. Other vasculitis with large vessel involvement and those with prominent pulmonary involvement (e.g., antineutrophil cytoplasmic antibody associated-vasculitis-associated vasculitis and etc.) have been excluded during initial diagnostic process and patients’ follow-up in the clinic.

All patients’ records were reviewed according to their demographic data, comorbidities, disease duration, and symptoms (Table 1). The patients were invited to perform TTE and pulmonary function tests and six-minutes walking test (6MWT). All patients were classified according to New York Heart Association (NYHA) functional class I–IV.

All echocardiography were performed by two expert echocardiologists. Erythrocyte sedimentation rate (ESR) test, as an index of disease activity based on Kerr criteria, was also performed within the days of echocardiographic assessment. The echocardiographic measurements were performed according to the recent European Society of Cardiology (ESC)/European Respiratory Society (ERS) criteria.8 We used Doppler measurement for estimation of peak tricuspid regurgitation velocity (TRV) as the main variable for categorizing probability of PH (not simply the estimated sPAP) as follows: (1) TRV>3.4m/s or 2.9–3.4 in the presence echocardiographic signs suggesting PH from at least two different categories was considered high probability PH, (2) TRV of 2.9 to 3.4 or greater than 2.8 was considered intermediate, and (3) TRV≤2.8 or not measurable was considered low probability.

TAPSE was measured on M-mode images as the difference in RV basal motion from peak systole to end-diastole. sPAP was calculated from peak tricuspidal jet velocity using the simplified Bernoulli equation by adding the estimated right atrial pressure (eRAP) to the systolic trans-tricuspid pressure gradient. RA pressure (RAP) was estimated based on the inferior vena cava (IVC) end-expiratory diameter and collapsibility at the end-inspiratory phase, as recommended.8 The TAPSE/sPAP ratio was then calculated for all patients. Patients with high probability of PH scheduled to undergo Computed tomography pulmonary angiography (CTPA) to exclude other causes of pulmonary arterial lesions especially chronic thromboembolic pulmonary hypertension (CTEPH). If clinically indicated, right heart catheterization (RHC) on resting was undertaken to confirm the presence and classification of PH (group II or IV): mean pulmonary arterial pressure (mPAP)≥20mm Hg at rest and pulmonary vascular resistance≥3 Wood units and pulmonary artery wedge pressure≤15mm Hg were defined as pre-capillary PH.7

Additionally, all patients underwent pulmonary function tests including measurement of dynamic lung volumes, residual volumes (RV), total lung capacity (TLC), and diffusing capacity of the lung for carbon monoxide (DLCO). The results of PFTs were used as an adjunct modality in order to assess cardiopulmonary symptoms such as dyspnea or cough in the patients and to investigate other possible parenchymal or airways causes contributing to increased systolic pulmonary artery pressure.

We conducted also a comprehensive review of the English language literature published in the Medline/PubMed and Scopus database since 1960 with the following keywords: “Takayasu Arteritis”, “Pulmonary Arteritis”, “pulmonary involvement”, and “Pulmonary Hypertension”. A total of 36 studies focusing on incidence of Takayasu arteritis and its pulmonary manifestations were included. We excluded: (1) studies without a clear data on both of PAI and PH frequencies, (2) Case reports including those which had reported the cases with an isolated pulmonary involvement, (3) the studies conducted in the same center during close period of times, and (4) studies without a clear data on symptomatic status of patients. A total of 11 studies were enrolled and summarized in Table 2.

From January 2016 to December 2019, the records of 34 patients with Takayasu arteritis were extracted. Four patients were excluded from the study; one with a trivial TR jet signal, two lost follow-ups, and one patient died due to septic shock. Finally, a total of 30 patients were enrolled. All patients were female (100%) with a mean age of 40±9.3 years. The mean disease duration from diagnosis was 111±67 months. Demographic and echocardiographic features of TA patients are summarized in Table 1. Four (13%) patients met the criteria for high probability of PH (TRV: 4±0.92); the median systolic pulmonary artery pressure (SPAP) was 67 (76.7±37)mmHg. There were no significant differences between TA patients with and without PH, in terms of age (38.2±5.6 vs. 40.3±9.8; p=0.64), body mass index (BMI) (26.3±3.9 vs. 25.1±6.1; p=0.58), and disease duration (111±38.4 vs. 112±70.8; p=0.76). Regarding ESR level, there was no significant difference between the PH and non-PH group (p=0.57), as well as, among group with impaired Function Class (FC 2 and 3) and those without limitation in activity (FC 1) (p=0.30).

Out of all patients, six (20%) had respiratory symptoms: dyspnea in four patients (13%) and cough in three (10%) patients. Out of all patients, four patients were in NYHA FC 3 (13%) with a mean TRV: 3.9m/s which all meet TTE criteria for PH; six patients (20%) were found to be in NYHA FC 2. Only one case with a TRV: 3.1m/s and FC 2 was categorized in TTE as intermediate PH probability.

There were also significant differences among patient in FC 2 and FC 1 in term of BMI (26±4.4 vs. 22.1±3.1, p=0.045), 6MWT (375±43 vs 462±60, p=0.004), TAPSE (24±2.7vs. 20.3±3.1, p=0.032), respectively. TAPSE/SPAP had a meaningful difference between FC 1 and 2 (1.2±0.16 vs 0.83±0.24, p=0.018). Moreover, among these 3 groups of FC, the meaningful differences in term of the echocardiography and PFTs index were observed (Table 3).

In Spearman rank test, TAPSE as an indicator of right ventricle overload was also correlated with FEV1/FVC (r=0.446, p=0.043). TAPSE/SPAP was also correlated with vital capacity (r=0.458, p=0.028).

According to 6MWT, TA patients with <440m (56%) compared to those with >440m had lower FEV1 (p=0.009). Additionally 6MWT showed correlations with FEV1 (p=0.003, r=0.526), DLCO (p=0.028, r=0.41) and tend to be correlated with TAPSE in Takayasu arteritis patients (p=0.057, r=0.394).

In the group with high-probability PH, no significant obstructive abnormality in PFT or cardiac valvular affection were found justifying the increased pulmonary pressure. Thus, the patients were classified under the group 4 pulmonary hypertension due to pulmonary arteritis.7 RHC was only indicated in a 35-year-old patient with TRV of 4.3m/s and a reduced ejection fraction (20%) which underwent RHC, in which mPAP was 46mmHg, pulmonary vascular resistance (PVR) was 15.5 Wood Unit and pulmonary artery wedge pressure (PAWP) was 15mmHg. This confirmed a diagnosis of a pre-capillary PH as the primary cause of systolic dysfunction. Because of normal PAWP, she was started on Bosentan 125mgBid.

None of the enrolled patients had a prior history of a significant pulmonary disease or on any pulmonary-related drugs. Based on PFTs, no significant obstruction was found. In our patients with high-Probability PH, the mean value of DLCO were 62% of predicted which is considered a mild decrease based on the severity classification. FEV1% (71.5±5.8 vs. 87.5±13.3; p=0.015) and DLCO (58.7±13.3 vs. 88±16.3; p=0.003) were also significantly lower in the PH group.

This study had some limitations. First, due to the rare nature of the disease, the sample size was relatively small. Also, the diagnosis of PH was mainly dependent upon echocardiography and we were not able to perform RHC as the gold standard to confirm all PH diagnosis.

The incidence of PH in Takayasu arteritis was not uncommon complication, and comparable to incidence of respiratory symptom. Therefore, it seems reasonable to lower the screening threshold preferably initiated at younger ages or in new onset patients or in Takayasu patients with pulmonary symptoms and altered functional capacity. TAPSE/sPAP could be used for early PH probability risk stratification in TAs in association with functional capacity. However, further studies are needed to determine prognositic value of TAPSE/sPAP in Takayasu vasculitits.

The protocol for the research and data collection was approved by the Institutional Ethics Committee (Approval ID: IR.TBZMED.REC.1397.388).

Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article.