Diabetes Independently Associated With Increased Pulmonary Pressure, Decreased Right Ventricle Load Stress

Genetic risk for diabetes is the sole significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress, according to the results of a study published in the Journal of the American Heart Association.

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Pulmonary hypertension (PH) often leads to reduced quality of life and increased mortality, as elevated pulmonary pressures impart an increased afterload on the right ventricle (RV), which ultimately leads to ventricular failure and death.

Prior research had not fully investigated which clinical comorbid conditions are the primary causative drivers of pulmonary vascular remodeling or right heart dysfunction, according to the authors of the current study. To address this, investigators sought to use an unbiased approach to identify clinical diagnoses and comorbidities that share genetic risk with estimated pulmonary pressure.

Study participants were comprised of BioVU enrollees of European ancestry referred for echocardiography at Vanderbilt University Medical Center between 2004 and 2019. A patient was included if they had at least 1 echocardiogram with a reported right ventricular systolic pressure (RSVP), tricuspid regurgitant velocity (TRV), or measure of right ventricular function by tricuspid annular plane systolic excursion (TAPSE). A total of 14,861 participants of White European ancestry with at least 1 echocardiogram were available for the study after any exclusions.

Investigators first aimed to determine an unbiased method to examine which clinical diagnoses shared potential genetic architecture with estimated RVSP by echocardiography. Using Bayesian sparse linear mixed modeling, they found the top 2 International Classification of Diseases Ninth Revision (ICD9) codes associated with a predictor of RVSP were codes for diabetes.

The researchers then sought to flesh out the full extent to which diabetes and associated metabolic risk factors may share genetic architecture with pulmonary pressure. They found a strong association between genetic risk for diabetes and BMI and highest estimated RVSP or TRV (RSVP: β = 0.011 +/- 0.003 for diabetes, β = 0.015 +/- 0.003 for BMI; TRV: β = 0.016 +/- 0.005 for diabetes, β = 0.02 +/- 0.005 for BMI).

Next, investigators sought to examine the genetic relationship among pulmonary pressure, diabetes, and obesity using 2-sample univariate Mendelian randomization (MR). A significant association between exposures of diabetes and obesity and outcomes of highest RVSP and TRV was found (RVSP: β = 0.015 +/- 0.006 for diabetes, β = 0.056 +/- 0.012 for BMI; TRV: β = 0.025 +/- 0.009 for diabetes, β = 0.075 +/- 0.019 for BMI).

To account for factors that may affect pulmonary pressure, such as volume status, afterload, or acute decompensation, the study authors conducted a sensitivity analysis using both the first reported measure of RVSP or TRV for a given subject, which resulted in similar associations between the risk of diabetes and obesity and pulmonary pressure.

Continuing, the investigators repeated their analysis using binary thresholds for RVSP (33 mm Hg, 40 mm Hg, and 50 mm Hg) in a MR analytic framework. The association between BMI and diabetes and PH remained significant and grew larger with higher thresholds for defining PH.

Lastly, the study investigators sought to better understand the extent to which metabolic risk factors may share genetic architecture with measures of right ventricular adaptation to load stress. Using univariable MR analysis, they found a significant association between diabetes and lower TAPSE/RVSP, but no significant association between obesity and TAPSE/RVSP.

In a commentary regarding the study, Felipe Kazmirczak and Kurt W. Prins recognized the new discoveries found by the study authors but posed multiple inquiries for future research. These include analyzing whether this association applies to more diverse populations, whether the duration and severity of diabetes modulates its relationship with pulmonary pressures and right heart function, and whether currently available diabetic therapeutics can improve RV-pulmonary circulation relationships if used in pulmonary hypertension.

“Certainly, clinicians will need to understand the best approaches to treat these complex patients as this study suggests we may be seeing a large influx of patients with diabetes in our pulmonary hypertension clinics in the near future,” Kazmirczak and Prins concluded.

References

Bagheri M, Agrawal V, Annis J, et al. Genetics of pulmonary pressure and right ventricle stress identify diabetes as a casual risk factor. J Am Heart Assoc. 2023;12:e029190. doi:10.1161/JAHA.122.029190

Kazmirczak F and Prins KW. Editorial: Diabetes enters stage right: genetic association studies suggest diabetes promotes pulmonary hypertension and right ventricular dysfunction. J Am Heart Assoc. 2023;12:e030954. doi:10.1161/JAHA.123.030954