To our knowledge, this is the first study comparing clinical characteristic between different hemodynamic phenotypes of CTD-PH, and the first study to describe the characteristic of a group of CTD-PH patients with PVR < 3WU and preserved CO (hyperdynamic PH), which was less severe considering hemodynamic and cardiac parameters, but with similar 5-year outcome compared with CTD-PAH. Patients with CpcPH tend to have higher mPAP and more obvious right ventricle enlargement. No significant difference in clinical characteristics nor survival were found in CTD-PAH patients regardless of whether they are combined with mild to moderate ILD.
CTD is a type of disease that affect multiple organs and systems. PH is one of the common complications of CTD, and can hamper prognosis. Although CTD-PH is currently a subcategory of WHO Group 1 PH, also known as PAH. According to our cohort, PAH is not the only hemodynamic phenotype of CTD-PH. Among the 218 patients who confirmed PH by RHC, 4.1% (9 cases) were PH caused by lung disease or hypoxia after assessment of lung function test and chest high-resolution CT, 0.9% (2 cases) were CTEPH according to CT pulmonary angiography, and finally 16.5% (36 cases) were PH caused by LHD with PAWP > 15mmHg confirmed by RHC. Since our hospital is a rheumatic disease referring center, it is highly likely that the non-PAH proportion, which caused by complications mentioned above, may be underestimated.
SSc-PH accounts for approximately 50–70% of CTD-PH in western large registries[4, 6], whereas PH associated with SLE is more common in China[23]. SLE, SS and SSc took up most of the CTD-PH patients in our cohort, prevalence of which are 49.8%,16.4% and 13.7%. PH develops much more uncommonly with RA, vasculitis, PM or DM[24, 25], and is rarely seen in patients with AOSD, only a few cases have been reported[26]. However, because of lacking large cohorts, prevalence of PH in patients with CTDs other than SSc remains to be further determined. In our cohort, 5 patients with AOSD, 4 patients with RA, 4 patients with systemic vasculitis and 3 patients with PM/DM have been included. Regarding the aspect of PH, these cases include not only PAH, but also PH due to left heart disease and lung disease. The exact pathophysiology of how PH develops in RA, PM/DM, AOSD or systemic vasculitis is yet unknown. As has been hypothesized with other CTDs, endothelial dysfunction and remodeling of pulmonary arteries, cardiac involvement, ILD, PE as well as immune dysregulation can all play a role.
Recently, attention has been driven to a group of patients with clearly elevated mPAP (≥ 25 mmHg) and without relevant LHD (PAWP ≤ 15 mmHg), who fail to fulfill the hemodynamic criteria of pre-capillary PH because of “normal” PVR (PVR ≤ 3 WU). A few studies have suggested that PVR ≥ 2WU is already associated with PH[9, 27]. Data of an article published by Panagiota Xanthouli et al[9] showed that patients with PVR ≥ 2WU who still have a preserved CO at rest (5.47 ± 1.11L/min, 95% CI 5.04-5.90L/min), have already presented with impaired exercise capacity, right heart function and worse prognosis. The result of our study also addresses this point. All 32 patients in hyperdynamic PH group exhibited low PVR (1.9 ± 0.6WU, 95%CI 1.7–2.2) and preserved CO (6.7 ± 1.4L/min, 95% CI 6.3-7.2L/min). No patients had co-existing conditions that can cause hyperdynamic circulatory state, such as pregnancy, hyperthyroid, severely anemia, or hepatic cirrhosis. Former studies focusing on right ventricle demonstrated that the right ventricle is very sensitive to afterload changes and its adaptation to chronic afterload involves increasing contractility[28]. Thus we hypothesized that PVR ≥ 2WU has already caused an increase in pulmonary circulation afterload, and the cardiac function is preserved or correspondingly increased at this time to compensate. When the cut off value for PVR is set too high (3WU), the elevated CO will be regarded as a "hyperdynamic" state.
The contribution of LHD to PH in CTD patients is not yet well established. Current data mostly comes from SSc-PH. Cardiac involvement is common in SSc. Studies have reported that myocardial fibrosis is the pathological hallmark of this complication, and has been proved by cardiac MRI as well as biopsies[5]. This can either explain the development of post-capillary PH or add post-capillary component to pre-capillary PH (CpcPH). Other CTDs, such as SLE, RA, PM/DM are also known to involve cardiac muscles, and can subsequently be associated with WHO Group2 PH. In our study, most patients classified as WHO Group2 PH have preserved ejection fraction (LVEF 68.5 ± 5.0%, 2 patients had LVEF between 40–45%), which is consistent with prior studies[10, 11]. Furthermore, we discovered that WHO Group2 PH is more likely to associate with mitral valve dysfunction than WHO Group1 PH. Although because of the low prevalence, valvular involvement is not considered a typical manifestation of SSc or SLE[29], but it could contribute to the development of PH in CTD patients. CpcPH demonstrated higher mPAP and right ventricle diameter than IpcPH, indicating a worse hemodynamic and structural state. Bourji KI et al reported CpcPH demonstrates worse survival[11]. However, Lammi MR et al[10] reported that survival was similar between IpcPH and CpcPH. Our study also failed to find difference in survival between these two groups. But more data is required to support this conclusion.
ILD is a frequent complication of CTD which can be detected by high-resolution CT and lung function test. Morrisroe K et al[12] found that ILD is an independent predictor of death in CTD-PH patients, and assumed that co-existence of ILD could lead to a more severe clinical phenotype. However, results from another study showed no association between the severity of ILD and hemodynamic profiles[13]. Michelfelder et al[14] compared SSc-PAH-ILD (n = 24) patients with SSc-PAH patients (n = 27), and did not find a difference in hemodynamic parameters, NT-proBNP levels, FVC/DLCO ratio, 6MW, WHO functional class and scleroderma-specific autoantibody levels between two groups, but a decreased survival rate in SSc-PAH-ILD patients. Consistent with former studies, our study found hemodynamics, echocardiogram parameters were of no significant difference regardless of the association with ILD. However, t is still under debate whether co-existing of ILD increases the risk of death in CTD-PH patients. And it seems HRCT, lung function test and RHC are not reliably enough to distinguish between WHO Group1 and 3 PH. Further studies are needed to answer these questions.
Our study also addresses the importance of carefully phenotyping PH in CTD-PH patients in order to provide the most appropriate treatment. 5 out of 7 CTD-PH patients with post-capillary PH were on PAH targeted therapy before RHC, and discontinued the medication after. This is probably because primary hospitals lack the condition to perform RHC, and weren’t aware of the diversity of hemodynamic types of CTD-PH. Furthermore, hemodynamic classification may change over time. As shown in PHAROS cohort, 30% of SSc-PAH experienced PAWP class change during follow-up[30]. 79.3% of CpcPH patients in our cohort were treated with PAH-targeted therapy after RHC. Although some recent studies[31, 32] showed patients with CpcPH and HFpEF may benefit from phosphodiesterase type 5 inhibitor, evidence from randomized trial is still needed to determine whether PAH-targeted therapy can be applied in CpcPH. In any case, CpcPH patients should be monitored closely and regularly repeat RHC when taking PAH-specific drugs.
What is the best approach to distinguish the non-PAH proportion in CTD-PH patients? After ruling out patients with severe LHD (LVEF < 35%), severe lung disease (FEV1 < 60% or FVC < 70% or signs of significant interstitial lung disease in HRCT of the lungs), and CTEPH (indication of pulmonary embolism on CTPA), still 68 patients (32.9%) cannot fit criteria for pre-capillary PH. Meanwhile, different forms of PH can overlap in one single patient and complicate the case. Unfortunately, our study failed to distinguish these patients in the perspective of CTD characteristics such as inflammatory markers and autoantibodies, except for anti-RNP positivity is lower in CTD associated with WHO Group 2 PH. Thus, a full work up of echocardiography, lung function test, chest CT, CTPA or V/Q scan and most importantly RHC is still necessary when assessing CTD-PH patients.
Our study has limitations that must be acknowledged. First of all, using only TTE as the only detection method for PH may miss patients with early PH[33]. Secondly, because this is a retrospective study, missing data were unavoidable. Thirdly, not all patients are included at the diagnostic RHC and some patients have already taken PH specific therapies, which could affect the results, since hemodynamic features can change during the course of disease. Lastly, the sample size of some subgroups is small and the risk for type 2 error exists.