Sphingolipids and Lung-Related Mortality: The Cardiovascular Health Study

Abstract Rationale Respiratory mortality accounts for more than 20% of total deaths worldwide. Recent studies suggest that six sphingolipid species are associated with decreased lung function, as measured by forced expiratory volume (FEV1) values and/or increased risk of COPD. We hypothesize that these specific sphingolipids are associated with increased risk of lung-related mortality. Methods This study examines sphingolipid and mortality data obtained late in life on 4,612 participants of the Cardiovascular Health Study, a prospective bi-racial cohort of older adults (median age of 72). Ceramides (Cer) with acylated fatty acids 14:0, 16:0, and 18:0 (Cer-14, Cer-16, Cer-18 respectively) and sphingomyelin (SM) with 14:0, 16:0, and 18:0 (SM-14, SM-16, SM-18 respectively) were quantified using liquid chromatography-tandem mass spectrometry and external calibration. We used multivariable Cox regression to examine associations of sphingolipids with three primary outcomes: respiratory mortality, lung cancer mortality, and pneumonia mortality (coded based on death certificates). We secondarily analyzed COPD mortality, a subset of respiratory mortality. Results After a median follow-up of 10.2 years, 4,099 total deaths had occurred, including 207 respiratory deaths, 171 lung cancer deaths, and 210 pneumonia deaths. Of the six sphingolipids examined, four (Cer-16, Cer-18, SM-16, and SM-18) were significantly associated with respiratory mortality and lung cancer mortality; no significant associations were seen with death due to pneumonia. For each 2-fold increase in each of these four sphingolipid species, the association with respiratory mortality and lung cancer mortality ranged from 50% higher to 4-fold higher (see Figure). No significant association was seen between Cer-14 or SM-14 and any of the respiratory outcomes. When examining 153 COPD-related deaths, a subset of the 207 respiratory deaths, the associations with Cer-16, Cer-18, SM-16, and SM-18 tended to be strengthened (see Figure). Conclusions Cer-16, Cer-18, SM-16, and SM-18 are associated with an increased risk of both respiratory mortality as well as lung cancer mortality but not death due to pneumonia. Further studies are needed to better understand the mechanistic role of sphingolipids in lung-related mortality.