Improvements in French Risk Strati�cation Score were Correlated with Reductions in Mean Pulmonary Artery Pressure in Pulmonary Arterial Hypertension: A Subanalysis of the Japan Pulmonary Hypertension Registry (JAPHR)

Background Since there was no previous report, we analyzed the relationship between French Risk Stratification parameters in pulmonary arterial hypertension (PAH) and mean pulmonary arterial pressures (mPAP) using Japan PH Registry (JAPHR) national-wide cohort. Methods We enrolled 108 patients with PAH from JAPHR from previous reported cohort and analyzed the relations between French Risk Stratification scores and hemodynamic improvements. Results The ratio meeting 0 to 4 French Risk Stratification score was 21.3%, 31.5%, 32.4%, 13.0%, and 1.9% at baseline, and 6.5%, 23.2%, 33.3%, 23.2%, 13.9% at follow-up, respectively. The improvements in the number of criteria met were associated both with mPAP at follow-up (p = 0.03) and with the improvements in mPAP (p < 0.001). Conclusion The improvements in French Risk Stratification may become a marker of improved hemodynamics including mPAP.


Abstract
Background Since there was no previous report, we analyzed the relationship between French Risk Strati cation parameters in pulmonary arterial hypertension (PAH) and mean pulmonary arterial pressures (mPAP) using Japan PH Registry (JAPHR) national-wide cohort.

Methods
We enrolled 108 patients with PAH from JAPHR from previous reported cohort and analyzed the relations between French Risk Strati cation scores and hemodynamic improvements.

Conclusion
The improvements in French Risk Strati cation may become a marker of improved hemodynamics including mPAP.

Background
In the ESC / ERS pulmonary hypertension (PH) guidelines, right atrial pressure (RAP) and cardiac index (CI) have been proposed as hemodynamic parameters for pulmonary arterial hypertension (PAH) risk strati cation [1].Before the advent of current pulmonary vasodilators, as PAH progresses and the right ventricle dilates and fails, the mean pulmonary arterial pressure (mPAP) declines, resulting in the poor survival of patients with PAH.Therefore, past guidelines for PAH treatment recommended normalization of right ventricular function as a treatment goal, which is de ned as RAP < 8 mmHg and CI > 2.5 L/min/m 2 .As a result, mPAP has been excluded as not only as a therapeutic target but also as a risk strati cation marker.Recently, the French registry group proposed the French Risk Strati cation for PAH, which includes RAP and CI as risk strati cation markers at the time of diagnosis and during treatment [2].
The reliability of these risk strati cation parameters has been supported in multiple conditions and registries [3].However, with the progress of therapeutic strategies, including combination therapy, recent clinical observations suggest the possibility that mPAP may be an independent treatment goal.Ogawa et al. [4] reported that the survival rate of patients with mPAP ≤ 46 mmHg at follow-up was signi cantly better than that of patients with mPAP > 46 mmHg in 141 patients with idiopathic/heritable PAH at 3 PH centers in Japan.Thus, we expected that the current treatment strategy of using combination therapy improves not only the CI but also mPAP during follow-up in patients with PAH.
In this study, we aimed to analyze the changes in French Risk Strati cation parameters and mPAP from baseline to the follow-up period using the Japan PH Registry (JAPHR) nationwide cohort.

Methods
Patients registered in the JAPHR before 2013 and who initiated PH-speci c treatment in or before March 2013 were included in the study.We extracted patients' clinical information on WHO FC / NYHA classi cation, 6-minute walking distance (6MWD), RAP, CI, and mPAP at baseline and at the rst follow-up visit which was already reported [5].We then categorized patients based on the number of risk strati cation criteria that each patient met: i.e., NYHA classi cation I/II, 6MWD > 440 m, RAP <8 mmHg, and CI >2.5 L/m 2 , both at baseline and at the rst follow-up.We also categorized patients into 3 groups based on the change in the number of criteria met between baseline and follow-up: improved (number of factors increased), unchanged (number of factors unchanged) and worsened (number of factors reduced).We compared the distribution of mPAP across these different risk groups using a Kruskal-Wallis test.Tests were all two-sided and p-values <0.05 were considered statistically signi cant.This study was approved by the ethics committee of International University of Health and Welfare (approval #5-19-11), and followed the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation.All patients provided written informed consent to participate.
Categorizing the patients into groups based on the change in the number of criteria met revealed that 58 (53.7%) improved, 30 (27.8%) were unchanged, and 10 (9.3%) worsened (Figure 1).This grouping was associated with both mPAP at follow-up (p=0.03) and the improvement in the mPAP at follow-up from baseline (p<0.001, Figure 3).

Discussion
The evaluation of French risk strati cation at baseline and follow-up in the JAPHR cohort revealed that the risk strati cation score correlated with mPAP at follow-up.It was also found that improvements in the risk strati cation score correlated with those in mPAP.
The most important point in this study is that improvement in the risk strati cation score and hemodynamic parameters are closely related, especially in mPAP, in the JAPHR cohort.NIH registry data [6] indicated that not only increased RAP and decreased CI but also increased mPAP were associated with increased mortality in patients with primary PH.However, until now, most randomized controlled trials found mPAP improvement to be a poor prognosis factor [7].One possible reason is that multiple monotherapy studies only showed minor improvements in mPAP, meaning that monotherapy itself has less capacity to improve mPAP.However, a report of triple combination therapy suggests that combination therapy including epoprostenol may improve not only the CI but also mPAP [8].In addition, a JAPHR study reported that 85% of patients on upfront combination therapy had a ≥ 20% reduction in mPAP at the follow-up period, resulting in bene cial outcomes [5].Therefore, in treatment with combination therapy, it is expected that lowering the risk strati cation score will lead to a hemodynamic improvement in pulmonary circulation associated with not only right ventricular function but also mPAP.Regarding a novel treatment algorithm targeting risk strati cation proposed in Nice 2018 [3], the results of the present study suggest that this algorithm improves not only risk strati cation scores but also mPAP.
This study has some limitations.First, this cohort has data from advanced PH centers in Japan; as previously reported, the mortality and lung transplant events were less frequent and the prognosis was better than those of existing reports [5].Therefore, it was di cult to verify any correlations between risk strati cation score and prognosis at the initial visit or follow-up, as reported previously in other studies.
However, absolute improvements in hemodynamics, as well as in right heart failure and symptoms contained in the risk strati cation score, may indicate that patients in this cohort had a better prognosis.Second, a decrease in mPAP sometimes originate from worsening heart failure or decreases in cardiac output.However, since the risk strati cation score includes indices such as CI and RAP, it is not expected that the decrease in mPAP was due to the progression in cardiac dysfunction.Moreover, only rare cases suffered from decreased mPAP associated with cardiac output impairment in our cohort because this cohort had better prognosis concomitant with hemodynamic improvements [5].Third, this study was conducted in the cohort up to 2013, and the number of cases was small compared to the original French report [2].However, compared with the French cohort, the distribution of patients in each risk score after the initial treatment did not differ, which validates the risk score in Japanese patients.Therefore, this study may contribute to the future universalization of evaluation methods for therapeutic interventions.

Conclusion
In conclusion, the assessment of risk strati cation score improvements, may become a novel marker of improved hemodynamics, including mPAP, in JAPHR.Relationship between the improvements in French risk strati cation score and mean pulmonary artery pressure A: mean pulmonary artery pressures in the 3 groups of patients according to the improvement in French risk strati cation score B: changes of mean pulmonary artery pressures on 3 groups of patients according to the improvement in French risk strati cation score Abbreviations PH: hypertension

Figures Figure 1 French 2
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