Chest

Chest

Volume 159, Issue 1, January 2021, Pages 302-310
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Pulmonary and Cardiovascular: Original Research
BMI Is Causally Associated With Pulmonary Artery Pressure But Not Hemodynamic Evidence of Pulmonary Vascular Remodeling

https://doi.org/10.1016/j.chest.2020.07.038Get rights and content

Background

There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH).

Research Question

Is BMI casually associated with pulmonary artery pressure (PAP) and/or markers of pulmonary vascular remodeling?

Study Design and Methods

The study design was a two-sample inverse-variance weighted Mendelian randomization. We constructed two BMI genetic risk scores from genome-wide association study summary data and deployed them in nonoverlapping cohorts of subjects referred for right heart catheterization (RHC) or echocardiography. A BMI highly polygenic risk score (hpGRS) optimally powered to detect shared genetic architecture of obesity with other traits was tested for association with RHC parameters including markers of pulmonary vascular remodeling. A BMI strict genetic risk score (sGRS) composed of high-confidence genetic variants was used for Mendelian randomization analyses to assess if higher BMI causes higher PAP.

Results

Among all subjects, both directly measured BMI and hpGRS were positively associated with pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Categorical analyses revealed BMI and hpGRS were associated with PVH but not PAH. Mendelian randomization of the sGRS supported that higher BMI is causal of higher systolic pulmonary artery pressure (sPAP). Sensitivity analyses showed sPAP-BMI sGRS relationship was preserved when either individuals with PAH or PVH were excluded. In the echocardiographic cohort, BMI and hpGRS were positively associated with estimated PAP and markers of left heart remodeling.

Interpretation

BMI is a modifier of pulmonary hypertension severity in both PAH and PVH but is only involved in the pathogenesis of PVH.

Section snippets

Study Subjects and Clinical Data

All analyses were carried out on data obtained from Vanderbilt University Medical Center’s deidentified electronic health record. Available data were obtained as a part of routine clinical practice, and the study was approved by Vanderbilt’s institutional review board. Methods for cohort creation have been published previously.9, 10, 11 The population referred for RHC consisted of individuals with existing genotyping on the Illumina Multi-Ethnic Global Array (MEGA) platform. The echocardiogram

Results

We identified 1,043 subjects with existing MEGA genotyping data who were referred for RHC, unrelated, and of European ancestry (52% men; age, 60 ± 14 years). In this population, 12% had PAH, 40% had PVH, 6% had PH because of lung disease, and 42% did not have PH. Demographics, comorbidities, and laboratory values of the RHC cohort stratified by BMI genetic risk score quartile are displayed in Table 1.

Discussion

The reported intersection of metabolic disease and PH prompted us to investigate the relationships of BMI and BMI genetic architecture with pulmonary hemodynamics. Both BMI and the BMI hpGRS were associated with higher pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Consistent with these hemodynamic associations, BMI and the BMI hpGRS were associated with PVH, but not PAH. Utilization of a BMI sGRS in Mendelian randomization analyses supported that higher BMI

Interpretation

Our findings suggest that higher BMI is not associated with pulmonary vascular remodeling but is causally associated with higher pulmonary artery pressure.

Acknowledgments

Author contributions: T. E. T. takes responsibility for the content of the manuscript, including the data and analysis. T. E. T., R. T. L., S. H., T. A., E. F.-E., Q. S. W., J. D. M., and E. L. B. were involved in the experimental design, execution, and analyses. T. E. T. and E. L. B. prepared the manuscript, and all authors gave critical review of the manuscript.

Financial/nonfinancial disclosures: None declared.

Role of sponsors: The sponsor had no role in the design of the study, the

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    • FUNDING/SUPPORT: This work was supported by the National Institutes of Health (NIH) [Grants HL146588-01, HL146588-01S1, HL125212-01]. The samples and/or dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10OD017985 and S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/.

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