Association of Elevated Plasma Endothelin-1 Levels With Pulmonary Hypertension, Mortality, and Heart Failure in African American Individuals: The Jackson Heart Study

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Abstract

Importance

Despite pathophysiological links between endothelin-1 and pulmonary vascular remodeling, to our knowledge, the association between plasma endothelin-1 levels and pulmonary hypertension has not been studied in the general population. Also, whether endothelin-1 can predict future heart failure and mortality, outcomes that are associated with pulmonary hypertension, in a population cohort is unclear.

Objective

To determine whether elevated plasma endothelin-1 levels are associated with pulmonary hypertension, mortality, and heart failure.

Design, Setting, and Participants

Data from the Jackson Heart Study, a longitudinal, prospective observational cohort study of heart disease in African American individuals from Jackson, Mississippi, were analyzed. The community population sample was limited to participants with detectable tricuspid regurgitation on echocardiography. The study participants included self-identified African American individuals with plasma endothelin-1 levels and tricuspid regurgitation on echocardiogram (n = 3223) at the time of first examination (2000-2004). The analysis of the data began on April 14, 2014, and was completed on February 23, 2016.

Exposure

Log-transformed plasma endothelin-1 level.

Main Outcomes and Measures

Cross-sectional analysis: presence of pulmonary hypertension (defined as an elevated pulmonary artery systolic pressure >40 mm Hg on echocardiogram). Longitudinal outcomes were all-cause mortality (median follow-up, 7.75 years) and heart failure admissions (median follow-up, 5.32 years).

Results

Of the 3223 participants enrolled in the study, 1051 were men (32.6%). Mean (SD) endothelin-1 levels were 1.36 (0.64) pg/mL; 217 of 3223 cohort members (6.7%) had pulmonary hypertension. After adjusting for potential confounders, log-transformed endothelin-1 levels were associated with increased odds of pulmonary hypertension (adjusted odds ratio per log increment in endothelin-1, 1.66; 95% CI, 1.16-2.37). Log-transformed endothelin-1 levels were associated with mortality (adjusted hazard ratio per log increment in endothelin-1, 1.69; 95% CI, 1.27-2.25; median follow-up, 7.75 years) and heart failure (adjusted hazard ratio per log increment in endothelin-1, 1.57, 95% CI, 1.05-2.37; median follow-up, 5.32 years) in the study cohort. Phenotyping by pulmonary hypertension and endothelin-1 level showed mortality decreasing in order from subgroup with pulmonary hypertension and high endothelin-1 (high endothelin-1: ≥1.7 pg/mL; upper quartile); pulmonary hypertension and low endothelin-1 <1.7 pg/mL; lower 3 quartiles); no pulmonary hypertension and high endothelin-1; and no pulmonary hypertension and low endothelin-1 (log-rank χ2 = 77.16; P < .01 ).

Conclusions and Relevance

Elevated plasma endothelin-1 levels, especially associated with an elevated pulmonary artery systolic pressure on echocardiogram, may identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies.

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