Predictive Value Of Smoking Index Combined With NT-proBNP For Severity Of Pulmonary Hypertension And Related Laboratory Studies

Objective: 1.To analyze the smoking status of patients with pulmonary hypertension（PH）,construct a prediction model,and evaluate the combination of smoking index（SI）and NTN-terminal probrain natriuretic peptide（NT-proBNP）to predict the severity of PH.2.To preliminarily study the effects of nicotine,the main toxic component of cigarette smoke exposure,on the heart and lungs of mice,and to provide theoretical basis for scientific smoking cessation and prevention and treatment of pulmonary hypertension.Methods:Part 1: Case data of adult inpatients diagnosed with PH in the First Hospital of Shanxi Medical University from January 2020 to December 2021 were retrospectively collected,including the basic information of the patients,electrolyte related indexes,blood cell analysis related indexes,arterial blood gas analysis related indexes,coagulation function test related indexes,myocardial markers related indexes,and echocardiography related indexes were included.Univariate analysis was used to analyze the effect of smoking on PH,Spearman correlation analysis was used to analyze the correlation between SI and the severity of PH,receiver operating characteristic curve（ROC curve）was used to evaluate the diagnostic value of SI for the severity of PH.Part 2: To further confirm the relationship between smoking and PH occurrence and severity,we established a mouse model of PH with nasal nicotine administration,forty male C57BL/6J mice aged 5 weeks were randomly divided into 4 groups,10 mice in each group: Control group（sterile water for injection）,0.02 mg/kg/d nicotine low dose group,0.2 mg/kg/d nicotine medium dose group,2 mg/kg/d nicotine high dose group,the volume of nasal droplets was calculated based on the body weight of the mouse per gram per microliter,and the mice were given nasal drip at 17 o ’clock every day for 8 weeks.Log-rank（Mantel-Cox）test was used to compare the survival of mice in each group,HE staining was used to observe the pathological changes of pulmonary arteries in each group,and cardiac structure and function indexes were measured by small animal cardiac ultrasound scanner.Results:Part 1: According to the inclusion and exclusion criteria,1273 PH patients were finally included,with the median age was 69 years old and the median length of hospital stay was 11 days,the majority of patients were male（56.10%）,36.50% had a history of smoking,and the majority of PH patients included were group 2 PH（33.20%）and group 3 PH（32.40%）.Male smoking patients were significantly more than female patients（P < 0.001）,smoking patients had a history of drinking alcohol was significantly more than non-smoking patients（P < 0.001）,smoking patients had a history of diabetes and hypertension was significantly lower than non-smoking patients（P < 0.05）,and the number of group 3 PH in smokers was significantly more than that in non-smokers.The number of patients with group 1 PH and group 5 PH was significantly less than that of non-smokers（P < 0.001）,and the differences were statistically significant.The effect of smoking on PH patients results showed that the severe disease rate of smoking PH patients was significantly higher than that of non-smokers（P = 0.013）,smoking patients of hemoglobin,hematocrit,arterial carbon dioxide partial pressure（PaCO₂）,activated partial thromboplastin time（APTT）,Right ventricular diameter（RVD）,tricuspid regurgitation velocity（TRV）,and pulmonary arterial systolic pressure（PASP）levels were significantly higher than those of non-smoking patients（P < 0.05）,smoking patients of platelet count,Cl-,arterial oxygen saturation（SaO₂）,arterial partial pressure of oxygen（PaO₂）,blood glucose（GLU）,N-terminal probrain natriuretic peptide（NT-proBNP）,and Left atrial diameter（LAD）were significantly lower than those in non-smoking patients（P < 0.05）,PH patients with severe disease were significantly younger than those non-severe patients（P = 0.009）,smoking and drinking rates were significantly higher in severe PH patients than those in non-severe PH patients（P < 0.05）,the number of severe group 2 PH patients were significantly less than that of non-severe group 2 PH patients,the number of severe group 4 PH patients was significantly higher than that of non-severe group 4 PH patients（P < 0.05）,patients with severe PH of SI,neutrophilic granulocyte percentage,red cell volume distribution width,hemoglobin,hematocrit,prothrombin time（PT）,APTT,thrombin time（TT）,NT-proBNP,cardiac troponin I（cTnI）,RVD,TRV and PASP levels were significantly higher than those in non-severe patients（P < 0.05）,patients with severe PH of lymphocyte percentage,platelet count,SaO₂,PaO₂,Left ventricular end-diastolic diameter（LVIDd）,Left ventricular end-systolic diameter（LVIDs）,and Fractional shortening（FS）levels were significantly lower than those in non-severe patients（P < 0.05）,and the differences were statistically significant;Correlation analysis showed that after adjusting for confounding factors,SI was positively correlated with hemoglobin（r_s = 0.191）and hematocrit（r_s = 0.176）,and negatively correlated with platelet count（r_s =-0.060）,PaO₂（r_s =-0.070）and NT-proBNP（r_s =-0.082）;ROC results showed that the area under the curve of SI（AUC = 0.533）was greater than that of NT-proBNP（AUC = 0.413）,and the combination of SI and NT-proBNP had the highest diagnostic value（AUC = 0.564）.The results of the effect of smoking on patients with group 3 PH showed that,among 413 of group 3 PH patients included in the study,male patients were the majority（68.77%）,53.75% of the patients had a history of smoking,and the smoking patients with non-mild group 3 PH were significantly more than non-smokers（P = 0.034）,the levels of red blood cell,hemoglobin,hematocrit,PaCO₂,APTT and LAD in smoking patients were significantly higher than those in non-smoking patients（P < 0.05）,the Body Mass Index（BMI）and platelet count levels of smoking patients were significantly lower than those of non-smoking patients（P = 0.031）,the smoking rate of non-mild patients were significantly higher than that of mild patients（P = 0.034）,patients with non-mild PH of SI,red cell volume distribution width,red blood cell,hematocrit,PaCO₂,APTT,cardiac troponin T（cTnT）,cTnI,RVD,Left ventricular posterior wall thickness（LVPWd）,TRV and PASP levels were significantly higher than those in mild patients（P < 0.05）,the platelet count,NT-proBNP,Interventricular septal thickness（IVST）and LVIDs levels in non-mild patients were significantly lower than those in mild patients（P < 0.05）;Correlation analysis showed that after adjusting for confounding factors,SI was positively correlated with red blood cell（r_s = 0.128）,hematocrit（r_s = 0.210）,PaCO₂（r_s = 0.120）and APTT（r_s = 0.098）;ROC analysis showed that the area under the curve of SI（AUC = 0.569）was similar to the area under the curve of NT-proBNP（AUC = 0.588）,and the combined of SI and NT-proBNP had the highest predictive value（AUC = 0.608）.These results indicate that smoking affects the severity of PH,and SI combined with NT-proBNP can be used as a predictive model for the severity of PH.Part 2: With the increase of intervention time,the activities of the three groups of nicotine intervention mice decreased,and the body weight decreased,in addition,the mice in the 2 mg/kg/d nicotine group showed obvious systemic severe toxic reaction with high nicotine level during nasal drops.In general,with the intervention process,the weight of mice in the sterile water for injection control group increased gradually,the weight of the 0.02 mg/kg/d,0.2 mg/kg/d,and 2mg/kg/d nicotine intervention groups increased slowly with time,and the weight was negatively correlated with the dose of nicotine intervention,the differences were statistically significant（P < 0.05）.The weight of 0.02 mg/kg/d and 0.2 mg/kg/d nicotine intervention groups increased slowly in the first five weeks,decreased in the sixth week,and increased significantly in the seventh week compared with the sixth week,the differences were statistically significant（P < 0.05）.The weight of mice in 2 mg/kg/d nicotine high dose group group increased slowly in the first four weeks,from the fifth week,the body weight showed a downward trend,and the weight increased significantly in the seventh week compared with the sixth week,and increased significantly in the seventh week compared with the sixth week,the difference was statistically significant（P < 0.05）;By Logrank test,the mortality rate of 2 mg/kg/d nicotine high dose group was higher than that of other groups,and the difference was statistically significant（P = 0.018）.Non-parametric test（Kruskal-Wallis H）or analysis of variance was used to analyze the echocardiographic parameters of the four groups of mice,the results showed that the Left ventricular posterior wall end-systolic diameter（LVPWd）of the control group and 0.2 mg/kg nicotine medium dose group were significantly smaller in the 0.02 mg/kg nicotine low dose group group mice,and the Left ventricular posterior wall end-diastolic diameter（LVPWs）in 0.02 mg/kg nicotine lowdose group group mice was significantly larger than that in control group mice,the differences were statistically significant（P < 0.05）;HE results showed that pulmonary artery wall thickness increased with the increase of nicotine intervention dose,and the difference was statistically significant（P = 0.0023）.Conclusions:1.SI can predict the severity of PH,which is a potential non-invasive predictive marker,SI combined with NT-proBNP can significantly improve the predictive value of the recognized PH marker NT-proBNP,and has a good clinical application prospect.2.Smoking is a risk factor for PH,and its main toxic component nicotine can cause pulmonary vascular remodeling and cardiac dysfunction,promote the occurrence and development of PH,which is related to the severity of PH,and provide a theoretical basis for scientific smoking cessation.