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Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

CMJ-2023-3022
10.1097/CM9.0000000000003263
00019
3
Correspondence
Obesity paradox in pulmonary hypertension secondary to chronic lung diseases
Wu Changwei 1
Wu Wenhui 2
Luo Cijun 2
Qiu Hongling 2
Wang Lan 2
Zhao Qinhua 2
Gong Sugang 2
Li Huiting 2
Xu Jian 2
He Jing 2
Liu Jinming 2
Pan Xiangxiang
1 Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
2 Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
Correspondence to: Jinming Liu, Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507, Zhengmin Road, Shanghai 200433, China E-Mail: jinmingliu2013@126.com
20 8 2024
20 9 2024
137 18 22602262
29 12 2023
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

OPEN-ACCESSTRUE
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pmcTo the Editor: Obesity, which has currently become an important public health problem, has been considered a positive prognostic factor for patients with multiple chronic disorders, including pulmonary arterial hypertension, a phenomenon known as the “obesity paradox”.[1] However, whether this phenomenon exists in pulmonary hypertension (PH) secondary to chronic lung disease (CLD-PH) remains unknown. This study aimed to elucidate the association between body mass index (BMI) and mortality in CLD-PH patients.

The study was approved by the Shanghai Pulmonary Hospital Ethics Committee (K12-091), and all participants provided written informed consent. A total of 506 patients aged 18–88 years, who admitted to the Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital from October 2008 to November 2022 and diagnosed with CLD were retrospectively evaluated. Patients with other types of PH and those with missing data were excluded. At last, 399 patients newly diagnosed with CLD-PH were enrolled [Supplementary Figure 1, http://links.lww.com/CM9/C113].

Pre-capillary PH was based on right heart catheterization (RHC) according to the 2022 European Society of Cardiology/European Respiratory Society PH guideline,[2] whereas CLD, which included chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), bronchiectasis, and interstitial lung disease (ILD). After ruling out other causes of PH, the diagnosis of PH secondary to CLD was established by at least two experienced PH experts.

Demographics, anthropometrics, date of diagnosis, World Health Organization (WHO) functional class, hemodynamic parameters based on RHC, and laboratory tests including liver, renal function, N-terminal pro-brain natriuretic peptide (NT-pro BNP), triglyceride, and cholesterol, were extracted from medical records using a standardized data collection form. RHC was performed at baseline in all subjects at time of the first hospitalization. The mean right atrial pressure (mRAP), mean pulmonary artery pressure (m PAP), pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), and cardiac output (CO), as well as mixed venous oxygen saturation (SvO2), were calculated. The cardiac index was calculated as the ratio of CO to the body surface area. BMI was calculated by dividing the patient’s weight in kilograms by the square of their height in meters. The patients were classified into three groups based on their BMI, following the criteria established by the WHO[3]: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to <25.0 kg/m2), overweight and obese (BMI ≥25.0 kg/m2). All data were checked by two physicians independently and a third researcher adjudicated any difference in interpretation between the two primary reviewers.

Continuous variables were presented as median (Q1–Q3) or mean ± standard deviation, and categorical variables were presented as number with percentage. Differences between baseline variables were evaluated using a one-way analysis of variance, Kruskal–Wallis H, or χ2 statistic as appropriate. Univariable and multivariable Cox proportional hazards models were created to assess the prognostic relevance of BMI for survival and evaluate the hazard ratios (HRs) for all-cause mortality with 95% confidence intervals (CIs). Multivariable Cox proportional hazards models were constructed in CLD-PH patients and subgroups according to the BMI categories: one Cox proportional regression analysis adjusted for age and gender; the other adjusted for age, gender, and hemodynamics indices (CO, PVR, SvO2, and m PAP). Survival curves were derived by the Kaplan–Meier method with right censoring (Type III censoring) and compared by the log-rank test. The detailed methods are provided in the Supplementary Material, http://links.lww.com/CM9/C113. All analyses were performed using SPSS version 22.0 (Statistic Package for Social Science, IBM, Armonk, NY, USA) and R version 4.3.0 (https://www.r-project.org/), with a P-value <0.05 indicating statistical significance.

Among the included patients (mean age, 62 ± 12 years), 161 (40.35%) were female. The majority of the patients (55.14%, 220/399) were in the normal weight group, whereas 99 (24.81%) patients were in the underweight group, the other 80 (20.05%) patients were in the obese and overweight group. Baseline demographic and clinical characteristics are shown in Supplementary Table 1, http://links.lww.com/CM9/C113. COPD (67.67%, 270/399) was the most frequent etiology of CLD-PH, with the prevalences 64.65% (64/99), 65.91% (145/220), and 76.25% (61/80) in underweight, normal weight, and overweight and obese groups, respectively. Among the three groups, underweight patients had the lowest CO and SvO2 (P = 0.001 and 0.008) and the highest PVR (P = 0.007). Intriguingly, the overweight and obese group had the opposite results (i.e., highest CO and SvO2 and lowest PVR). No statistically significant difference in m PAP was observed among three groups (P = 0.850, Supplementary Table 2, http://links.lww.com/CM9/C113). In terms of nutritional and metabolic indicators [Supplementary Table 3, http://links.lww.com/CM9/C113], the underweight group had the lowest levels of red blood cell, hemoglobin (HGB), glucose (GLU), albumin (ALB), creatinine (CR), uric acid (UA), triglyceride (TG), and low-density lipoprotein (LDL), and the highest level of NT-pro BNP (all P <0.05).

The median follow-up was 24 months (Q1–Q3: 10–43 months), 127 (31.83%) patients died during follow-up, and the main causes of death were COPD (21.3%). The 1-year, 3-year, and 5-year survival rates were 87.70%, 68.00%, and 54.10%, respectively. In the underweight group, the 1-year, 3-year, and 5-year survival rates were 81.10%, 53.10%, and 38.00%, respectively, which has the highest mortality among the three groups [Figure 1]. For COPD-PH patients, both overweight and obese and normal weight patients had lower mortality rate than those with underweight patients (P = 0.010 and 0.020 by log-rank analysis, respectively) [Supplementary Figure 2, http://links.lww.com/CM9/C113]. CLD-PH patients with overweight and obese had better survival rate than underweight (P = 0.006) and normal weight groups (P = 0.030, Supplementary Figure 3A, http://links.lww.com/CM9/C113) when they were under the age of 65 years. However, among patients with age ≥65 years, no statistically significant difference was observed among three groups [Supplementary Figure 3B, http://links.lww.com/CM9/C113]. Normal weight patients were used as the reference in Cox regression analysis. Univariable Cox proportional hazards analysis showed that underweight increased the risk of death in CLD-PH (hazard ratio [HR], 1.66; 95% confidence interval [CI]: 1.13–2.46; P = 0.010) [Supplementary Table 4, http://links.lww.com/CM9/C113]. In multivariable Cox model, when adjusted for age and gender, underweight was still associated with increased all-cause mortality rate (HR, 1.67; 95% CI: 1.13–2.47; P = 0.010). This association was robust after further adjusting for CO, PVR, SvO2, and m PAP (HR, 1.69; 95% CI: 1.13–2.55; P = 0.010) [Supplementary Table 4, http://links.lww.com/CM9/C113]. In COPD-PH patients, underweight increased the risk of death (HR, 1.92; 95% CI: 1.15–3.22; P = 0.010) [Supplementary Table 5, http://links.lww.com/CM9/C113]. Subgroup analysis showed a significantly increased risk of death in patients aged ≥65 years (HR, 2.07; 95% CI: 1.11–3.87; P = 0.020, Supplementary Table 6, http://links.lww.com/CM9/C113). Using adjusted fractional polynomial Cox regression models with BMI as a continuous variable, a J-shaped association with mortality was observed, with a significantly increased risk of death in patients and a trend to higher mortality after adjusting for age and sex [Supplementary Figure 4, http://links.lww.com/CM9/C113].

Figure 1 Kaplan–Meier curves and survival analysis in patients with PH secondary to CLDs categorized according to BMI. BMI: Body mass index; CLDs: Chronic lung diseases; PH: Pulmonary hypertension.

In our study, we evaluated the relationship between BMI and PH secondary to CLD. This analysis identified that there was an increase of mortality in patients who were underweight in the overall cohort, COPD-PH patients, and patients ≥65 years of age. Our study focused on the impact of BMI in PH patients secondary to CLD and demonstrated an “overweight paradox” in a real-world cohort of CLD-PH patients. The mechanism underlying the correlation between BMI and mortality in CLD-PH patients is not fully understood. In the present literature, underweight CLD-PH patients had lower levels of GLU, ALB, CR, UA, TG, and LDL, which suggests that their condition might have also been complicated with malnutrition and reduced skeletal muscle mass, potentially causing respiratory hypofunction, further worsening lung function and increasing mortality rates. In addition, malnutrition can also increase respiratory muscle atrophy and infection susceptibility, subsequently impairing lung function. Moreover, increased catabolic burden, cardiac cachexia, abnormal cytokine and neurohormonal secretion, impaired immune status, and lower socioeconomic status can also be considered the underlying mechanisms associated with being underweight and contribute to the high mortality in CLD-PH.[4] Given that almost 75% of the patients in our cohort were complicated with elevated levels of NT-pro BNP, we speculate that the proposed explanations for this obesity paradox in patients with heart failure may also refer to CLD-PH patients, such as the potentially greater metabolic reserve among overweight and obese patients, which can reduce disease-induced oxidative stress and systemic inflammation through endotoxin binding.[5] Moreover, overweight and obesity have been linked to decreased circulating levels of NT-pro BNP and higher CO, suggesting the presence of favorable ventricular function.[6] In our study, overweight and obesity group had better prognosis than underweight and normal weight groups in CLD-PH patients under 65 years old, which showed awareness should be raised regarding diet and nutrition in such patients. In the future, nutrition intervention strategies should be established to assist clinicians in caring for individuals with CLD-PH.

Our study has several limitations worth noting. First, we could not eliminate the possibility of regional specificity and selection bias given the retrospective nature and relatively small sample size from a single center. Hence, further studies were needed to validate the generalizability of our findings. Second, we only used a single method for measuring BMI to assess obesity, which would ignore the distribution of body composition (fat distribution or muscle content), so further study should be considered to fully evaluate the association of obesity with CLD-PH. Third, previous studies also observed higher mortality in PAH or COPD patients who were morbidly obese (BMI ≥35.0 kg/m2), and better outcome in obese patients, while in our study only 9 patients were morbidly obese and 21 were obese, so the relationship between obese and outcome still needs to be explored in future.

In summary, our results indicated that underweight increased the risk of death in CLD-PH patients, especially in patients aged ≥65 years. However, further research is needed to explore the underlying mechanisms and verify the practical application of such strategies in clinical practice.

Funding

This work was supported by the grants from the program of Shanghai Hospital Development Center (No.SHDC2020CR6016-002), the Program of National Key Research and Development Project of China (No. 2023YFC2509500), the Program of Natural Science Foundation of Shanghai (No. 22ZR1452400), the Pujiang Talent Program (No. 22PJD064), and the Program of Shanghai Pulmonary Hospital (Nos. FK18003 and FKLY20005).

Conflicts of interest

None.

Supplementary Material

Changwei Wu and Cijun Luo contributed equally to this work.

How to cite this article: Wu CW, Wu WH, Luo CJ, Qiu HL, Wang L, Zhao QH, Gong SG, Li HT, Xu J, He J, Liu JM. Obesity paradox in pulmonary hypertension secondary to chronic lung diseases. Chin Med J 2024;137:2260–2262. doi: 10.1097/CM9.0000000000003263
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