Clinical Study On The Application Of Non-invasive Examination In Risk Stratification Of Pulmonary Hypertensio

Part Ⅰ:Heart Rate Recovery at 1 Min after Exercise Is a Marker of Disease Severity and Prognosis in Chronic Thromboembolic Pulmonary HypertensionObjectives:Heart-rate recovery at 1 min(HRR1)is a widely used noninvasive marker for assessing autonomic nerve function,which is defined as decrease of heart rate within 1 min after exercise cession.Numerous studies have suggested that HRR1 is associated with clinical outcome in various cardiovascular diseases,including coronary artery disease,heart failure and pulmonary arterial hypertension(Group 1 pulmonary hypertension).However,its value in chronic thromboembolic pulmonary hypertension(CTEPH)remains unclear(Group Ⅳ pulmonary hypertension).The present study aimed to investigate the correlations between functional status/echocardiography/hemodynamics/prognosis and HRR1 in CTEPH.Methods:We retrospectively reviewed medical records of adult CTEPH patients who underwent right heart catheterization in Fuwai hospital,Chinese Academy of Medical Sciences between Jun 2014 and October 2020.Baseline characteristics including demographics 6-min walk distance,N-terminal pro-brain natriuretic peptide and World Health Organization functional class(WHO FC)were collected.The primary endpoint was clinical worsening.Results:A total of 188 CTEPH patients were enrolled.The mean age was 54.3±13.0 years old and 84 were female.The median(interquartile range)follow-up time was 16(8-24)months.A total of 45 patients experienced clinical worsening,including 6 death and 39 rehospitalization due to right heart failure or progression of pulmonary hypertension or addition of parenteral prostanoids.Spearman correlation coefficients showed that HRR1 was correlated with established markers reflecting patients’ functional status(e.g.,WHO FC,1=-0.234,P<0.001),echocardiographic parameters(e.g.,the ratio of right ventricular end-diastolic to left ventricular end-diastolic diameter,r=-0.359,P<0.001),hemodynamics(e.g.,cardiac index,r=0.289,P<0.001)and cardiopulmonary exercise testing parameters(e.g.,peak oxygen uptake,r=0.494,P<0.001).These correlations persisted even after adjusting for age,sex and body mass index by using multivariable linear regression.Meanwhile,the COMPERA 2.0 risk score increased as HRR1 decreased.Receiver operating characteristic curve analysis showed that,with the largest Youden-index,the optimal cutoff value for HRR1 in predicting clinical worsening events was 14 beats.Kaplan-Meier curve analysis showed that the clinical worsening-free survival rates were lower in patients with HRR1<14 beats at baseline.Univariable Cox analysis showed that HRR1≥14 beats was associated with long-term(follow-up time≥10 months)clinical worsening events(hazard ratio=0.305,95%CI=0.135-0.690).After adjusting confounders in multivariable Cox analysis,HRR1≥14 beats was still associated with clinical worsening events.Conclusions:Baseline HRR1 was associated established markers of disease severity of pulmonary hypertension.The COMPERA 2.0 risk score increased as HRR1 decreased.Baseline HRR1≥14 beats could independently predict long-term clinical outcome in patients with CTEPH.Part Ⅱ:Carbohydrate Antigen 125 Is a Marker of Disease Severity and Prognosis in Pulmonary HypertensionObjectives:Emerging evidence shows that Carbohydrate antigen 125(CA125)is a noninvasive marker which is closely associated with the severity and prognosis of various cardiovascular disease.However,its clinical significance in pulmonary hypertension remains unclear.The present study aimed to evaluate the associations between the serum levels of CA125 and functional status/echocardiography/hemodynamics/cardiopulmonary exercise testing/prognosis in patients with pulmonary hypertension.Methods:We retrospectively reviewed medical records of adult idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients who underwent right heart catheterization in Fuwai hospital,Chinese Academy of Medical Sciences between Jan 2014 and Jun 2020.Baseline characteristics like demographics 6min walk distance,N-terminal pro-brain natriuretic peptide and World Health Organization functional class(WHO FC)were collected.The primary endpoint was clinical worsening.Results:A total of 518 patients were enrolled(284 patients with idiopathic pulmonary arterial hypertension and 234 patients with chronic thromboembolic pulmonary hypertension).The mean age was 43.2±15.8 years old and 338 were female.The median(interquartile range)follow-up time was 24(10-38)months.A total of 215 patients experienced clinical worsening,including 28 death,157 rehospitalization due to right heart failure or progression of pulmonary hypertension and 30 addition of parenteral prostanoids.Spearman correlation coefficients showed that CA125 was correlated with established markers reflecting patients’ functional status(e.g.,WHO FC,r=0.242,P<0.001),echocardiographic parameters(e.g.,the ratio of right ventricular end-diastolic to left ventricular end-diastolic diameter,r=0.317,P<0.001),hemodynamics(e.g.,cardiac index,r=-0.227,P<0.001)and cardiopulmonary exercise testing parameters(e.g.,peak oxygen uptake,r=-0.296,P<0.001).These correlations persisted even after adjusting for age,sex and body mass index by using multivariable linear regression.Meanwhile,the COMPERA 2.0 risk score increased as the CA125 levels escalated.Receiver operating characteristic curve analysis showed that,with the largest Youden-index,the optimal cutoff value for CA125 in predicting clinical worsening events was 20 U/ml.Kaplan-Meier curve analysis showed that the clinical worsening-free survival rates were lower in patients with CA125≥20 U/ml at baseline.Univariable Cox analysis showed that CA125≥20 U/ml was associated with clinical worsening events(hazard ratio=1.626,95%CI=1.243-2.126).More importantly,patients with chronic thromboembolic pulmonary hypertension faced additional 15.9%risk of experiencing clinical worsening than patients with idiopathic pulmonary arterial hypertension(P for interaction=0.001).After adjusting for confounders in multivariable Cox analysis,CA125≥20 U/ml was still associated with clinical worsening events.COMPERA 2.0 combined with CA125≥20 U/ml is better than COMPERA 2.0 risk score alone in predicting clinical outcome(Harrell’s C-index:0.585 vs.0.573,P=0.017).Conclusions:Baseline CA125 levels were associated with established markers of disease severity of pulmonary hypertension.The COMPERA 2.0 risk score increased as the CA125 levels escalated.Baseline CA125≥20 U/ml could independently predict clinical outcome in patients with pulmonary hypertension.CA125 could improve the power of COMPERA 2.0 risk score in predicting clinical outcome.Part Ⅲ:Diagnostric and Prognostic Value of Ventilatory Power in Pulmonary HypertensionObjectives:Peak oxygen uptake mainly focuses on cardiac-derived blood flow and could not directly reflect peripheral perfusion.Minute ventilation/carbon dioxide output slope(VE/VCO2 slope)only illustrates ventilatory response to increased pulmonary perfusion during exercise but fails to take peripheral blood pressure into consideration.Ventilatory power(VP),defined as(peak systolic blood pressure)/(VE/VCO2 slope),is a noninvasive marker which could reflect both ventilation efficiency and peripheral blood flow.In the present study,we aimed to investigate the diagnostic and prognostic value of VP in pulmonary hypertension.Methods:We retrospectively reviewed medical records of adult idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients who underwent right heart catheterization and cardiopulmonary exercise testing in Fuwai hospital,Chinese Academy of Medical Sciences between September 2012 and December 2020.Echocardiography-suspected pulmonary hypertension patients with invasively measured mean pulmonary artery pressure(mPAP)<25 mmHg were also enrolled as control group.Baseline characteristics including demographics 6-min walk distance,Nterminal pro-brain natriuretic peptide and World Health Organization functional class were collected.The primary endpoint was clinical worsening.Results:A total of 679 patients were enrolled(177 patients with mPAP<25 mmHg,300 patients with idiopathic pulmonary arterial hypertension and 202 patients with chronic thromboembolic pulmonary hypertension).The mean age was 41.6±15.6 years old and 332 were female.The median(interquartile range)follow-up time was 21(8-37)months.A total of 192 patients experienced clinical worsening,including 17 death,146 rehospitalization due to right heart failure or progression of pulmonary hypertension and 29 addition of parenteral prostanoids.When differentiating patients with mPAP≥25 mmHg from those with mPAP<25 mmHg,tricuspid regurgitation velocity(TRV)was superior to VP.But the combination of TRV and VP demonstrated its superiority to TRV used alone.When differentiating patients with mPAP=21-24 mmHg from those with mPAP ≤20 mmHg,VP was superior to TRV,although the difference didn’t reach statistical significance.But the combination of TRV and VP demonstrated its superiority to TRV used alone.Spearman correlation coefficients showed that VP was correlated with established markers reflecting patients’ functional status,echocardiographic parameters,hemodynamics and cardiopulmonary exercise testing parameters.These correlations persisted even after adjusting for age,sex and body mass index by using multivariable linear regression.Meanwhile,the COMPERA 2.0 risk score increased as the VP levels decreased.Receiver operating characteristic curve analysis showed that,with the largest Youden-index,the optimal cutoff value for VP in predicting clinical worsening events was 3.84 mmHg.Kaplan-Meier curve analysis showed that the clinical worsening-free survival rate was lower in patients with baseline VP<3.84 mmHg.Uni variable Cox analysis showed that VP was associated with clinical worsening events(hazard ratio:=0.763,95%CI=0.670-0.869).After adjusting confounders in multivariable Cox analysis,VP was still associated with clinical worsening events.COMPERA 2.0 combined with VP<3.84 mmHg is better than COMPERA 2.0 risk score alone in predicting clinical outcome(Harrell’s C-index:0.589 vs.0.570,P=0.010).The more aggressive the treatment was,the greater improvement in VP was.Conclusions:VP could improve the predictive power of TRV in identifying overt pulmonary hypertension and borderline pulmonary hypertension.Moreover,VP could reflect disease severity and treatment response.Baseline VP could independently predict clinical outcome in patients with pulmonary hypertension.VP could improve the power of COMPERA 2.0 risk score in predicting clinical outcome.Part Ⅳ:The Value of COMPERA 2.0 Risk Assessment Model in Guiding Balloon Pulmonary AngioplastyObjectives:Risk stratification is integrated throughout the management of pulmonary hypertension.The COMPERA 2.0 4-stratum risk score,comprised of 3 noninvasive markers,has been demonstrated to be superior to the 3-stratum one in predicting clinical outcome and reflecting treatment response in patients with pulmonary arterial hypertension.The present study aimed to evaluate the usefulness of the original and modified COMPERA 2.0 4-stratum risk score in predicting the efficacy of balloon pulmonary angioplasty(BPA)and clinical outcome in patients with chronic thromboembolic pulmonary hypertension(CTEPH).Methods:We retrospectively reviewed medical records of adult chronic thromboembolic pulmonary hypertension patients who underwent BPA in Fuwai hospital,Chinese Academy of Medical Sciences between May 2018 and October 2021.Baseline characteristics including demographics,6-min walk distance,N-terminal pro-brain natriuretic peptide and World Health Organization functional class were collected.The primary endpoint was clinical worsening.The secondary endpoints were achieving low risk and mean pulmonary artery pressure(mPAP)<30 mmHg at follow-up.Based on the methods of dealing with decimal,we used three versions of COMPERA 2.0 to stratify patients:the original version(by rounding decimal to the nearest integer),the modified version(by rounding decimal to the next integer)and a hybrid version that fuses the original and modified versions.Results:A total of 175 patients were enrolled.The mean age was 60.1± 10.8 years old and 92 were female.The median(interquartile range)follow-up time was 16(8-29)months.A total of 26 patients experienced clinical worsening,including 2 death,11 appearance or worsening of signs/symptoms of right heart failure,7 rehospitalization due to right heart failure or progression of pulmonary hypertension and 6 unsatisfactory long-term clinical response.All versions of COMPERA 2.0 4-stratum model outperformed the 3-stratum one in discriminating the differences in echocardiographic and hemodynamic parameters,and clinical worsening-free survival rates.The original and hybrid 4-stratum models could independently predict the primary and secondary endpoints,and the hybrid version seemed to perform better.The first BPA session could significantly improve risk profiles.The COMPERA 2.0 risk score after the first BPA session could also predict clinical outcome.During the subsequent BPA sessions,the proportion of patients with a low and intermediate-low risk profile was increasing steadily.In patients with an intermediate-high or high risk profile at baseline,those who were improved to intermediate-low or low risk after the first BPA session had better clinical outcome than those who remained intermediate-high or high risk.The number of BPA sessions required to achieve low risk/mPAP<30 mmHg increased as the baseline risk score escalated.Conclusions:The COMPERA 2.0 4-stratum model outperformed the 3-stratum one in BPA-treated patients with CTEPH.The 4-stratum model,especially its hybrid version,could be used to predict clinical outcome before the initiation of BPA and monitor treatment response.