Paul N. Jensen

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Rationale: Lung-related mortality accounts for up to 20% of total deaths worldwide. Recent studies suggest that six sphingolipid species are associated with decreased lung function and increased risk of COPD. We hypothesized that these sphingolipids are associated with increased risk of lung-related mortality. Methods: Sphingolipid and mortality data was obtained from 4612 participants in the Cardiovascular Health Study, a prospective cohort of older adults (mean age 77). Ceramides (Cer-14, Cer-16, Cer-18) and sphingomyelins (SM-14, SM-16, SM-18) were measured in plasma. Multivariable Cox regression was used to examine associations of sphingolipids with three primary outcomes: chronic respiratory, lung cancer, and pneumonia mortality. Results: After a median follow-up of 10.2 years, 4099 total deaths had occurred, including 207 chronic respiratory deaths, 171 lung cancer deaths, and 210 pneumonia deaths. Of the six sphingolipids examined in this report, four (Cer-16, Cer-18, SM-16, and SM-18) were significantly associated with chronic respiratory mortality and lung cancer mortality; no significant associations were seen with death due to pneumonia. For every 2-fold increase in each of these four sphingolipid species, the association with chronic respiratory mortality and lung cancer mortality ranged from 50% to over 400% higher. When examining 153 COPD-related deaths, a subset of the 207 chronic respiratory deaths, the associations with these four sphingolipids strengthened. Conclusion: Cer-16, Cer-18, SM-16, and SM-18 are associated with a higher risk of both chronic respiratory mortality and lung cancer mortality but not pneumonia mortality. Further studies are needed to better understand the mechanistic role of sphingolipids in lung-related mortality.

Background: Lacunes are 3-15 mm cavities originating from small perforating artery disease and are a hallmark of cerebral small vessel disease (cSVD). Prior prevalence studies relied on manual rating, which is prone to inter-rater variability and cannot quantify volume. We applied deep learning to quantify lacunes in a diverse community-based cohort. Methods: In this cross-sectional analysis of 1,038 Multi-Ethnic Study of Atherosclerosis (MESA) participants, with longitudinal cognitive follow-up, we quantified lacunes, confirmed them with a trained rater, and classified them as deep or lobar. Regression models examined associations of lacunes with cardiovascular risk factors, other small vessel disease lesions, brain atrophy, and cognition. Structural equation modeling evaluated whether deep lacune burden mediated associations of age or Framingham All-Cardiovascular Disease (CVD) Risk Score with atrophy and cognition. Results: Overall, 182 participants (17.5%) had at least one lacune (deep: 9.2%; lobar: 9.6%). Hispanic participants had lower lacune burden than White participants. Age, Framingham All-CVD Risk Score, PREVENT 10-year Total CVD Risk Score, and hypertension were associated with overall and deep lacunes, while lobar lacunes showed no associations. Deep lacunes were associated with white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds, as well as SPARE-BA, SPARE-AD, and cortical and hippocampal atrophy. Deep lacunes were cross-sectionally associated with decreased global cognition and language/semantic performance, and longitudinally with accelerated executive function decline independent of count. Deep lacune burden significantly mediated associations of age and Framingham All-CVD Risk Score with SPARE-AD, SPARE-BA, and global cognition. Conclusions: In this multi-ethnic community-based cohort, deep lacune burden demonstrated stronger associations with vascular risk, other cerebral small vessel disease markers, brain atrophy, and longitudinal executive function decline than lobar burden. By providing a continuous measure of lesion volume, automated quantification captured information beyond lacune count.

Key Points: Sphingolipids with long fatty acids (16–18 carbons) were associated with all-cause and cardiovascular death in patients treated with hemodialysis. Sphingolipids with very-long fatty acids (20+ carbons) were associated with lower risk of all-cause and cardiovascular death in dialysis patients. Background: Patients with kidney failure on hemodialysis are at a higher risk for death, especially cardiovascular death. Statins (which improve outcomes in general populations) do not improve outcomes in dialysis patients. Sphingolipids are mechanistically associated with cardiovascular disease and may represent novel, modifiable risk factors for death in patients with kidney failure. We aimed to examine the associations of sphingolipids with death specifically in dialysis patients. Methods: Using data from the Hemodialysis (HEMO) Study (a multicenter factorial trial of dose and flux), we measured 16 sphingolipids (ceramides-16:0, 18:0, 20:0, 22:0, 24:0, and 24:1; hexosylceramides-16:0, 22:0, and 24:0; lactosylceramide-16:0; and sphingomyelins 14:0, 16:0, 18:0, 20:0, 22:0, and 24:0) at baseline only in 927 participants with available stored serum using targeted liquid chromatography–tandem mass spectrometry. The primary outcome was all-cause death, with physician-adjudicated cause (cardiovascular versus noncardiovascular) as a secondary outcome. We examined the associations of sphingolipids with death using Cox regressions, controlling the false discovery rate <5%. Results: Among 927 participants, the mean (SD) age was 57 (14) years; median (interquartile range) dialysis vintage was 1.9 (0.8–4.1) years. Over a median (interquartile range) follow-up of 2.4 (1.4–4.0) years, there were 376 deaths. Nine of 16 sphingolipids were significantly associated with death, including ceramide-16:0 (adjusted hazard ratio [aHR] 2.13 per two-fold higher concentration, 95% confidence interval, 1.48 to 3.06), and ceramide-22:0 (aHR per two-fold higher 0.59, 95% confidence interval, 0.44 to 0.79), with similar direction of associations for sphingomyelins. Twelve of 16 sphingolipids were associated with cardiovascular death, for example, ceramide-16:0 (aHR per two-fold higher 3.43, 95% confidence interval, 2.05 to 5.74). No sphingolipid was significantly associated with noncardiovascular death. Conclusions: In a dedicated study of patients with kidney failure on hemodialysis, sphingolipids with long-chain fatty acids were strongly associated with greater risk of death, especially cardiovascular death.

Key Points: Higher levels of sphingomyelin (SM) carrying fatty acid 16:0 were associated with a 69% increased risk of CKD. Higher levels of SM carrying fatty acid 24:0 were associated with 29% lower risk of rapid decline in kidney function and 33% higher eGFR. These findings support future efforts to explore pathways that explain how circulating SMs influence risk of kidney outcomes. Background: Few studies have assessed whether ceramides (Cer) and sphingomyelin (SM) species are associated with kidney health in community-based studies. We investigated associations of eight Cer and SM species with incident CKD (eGFR 3 ml/min per 1.73 m ² per year. After multivariable adjustment, higher levels of SM-16 were associated with greater risk of CKD (relative risk [RR], 1.69; 95% confidence interval [CI], 1.24 to 2.23), while higher levels of SM-24 were associated with lower risk of rapid decline in kidney function (RR, 0.71; 95% CI, 0.58 to 0.87). Higher levels of circulating SM-24 were also associated with higher eGFR (RR, 1.33; 95% CI, 0.47 to 2.18). Cer-16, Cer-20, Cer-22, Cer-24, and SM-20 were not associated with kidney health. Conclusions: Associations of Cer and SMs with kidney health differ based on the length of the acylated saturated fatty acid attached to the SM.

BACKGROUND: Growing evidence indicates that trimethylamine N -oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N -oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N -oxide (hazard ratio, 1.15 [95% CI, 1.09–1.20]; P P P P =0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF ( P N -oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF. REGISTRATION: URL: https://www.clinicaltrials.gov/ ; Unique identifiers: NCT00005133 and NCT00005487.

Background: A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population. Methods and Results: The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long‐chain (ie, 16:0) and very‐long‐chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001–2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4‐year follow‐up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44–1.96) for ceramide‐16 (Cer‐16), 0.82 (95% CI, 0.71–0.95) for Cer‐20, 0.60 (95% CI, 0.51–0.70) for Cer‐22, 0.67 (95% CI, 0.56–0.79) for Cer‐24, 1.80 (95% CI–1.57, 2.05) for sphingomyelin‐16 (SM‐16), 0.54 (95% CI, 0.47–0.62) for SM‐20, 0.50 (95% CI, 0.44–0.57) for SM‐22, and 0.59 (95% CI, 0.52–0.67) for SM‐24. Conclusions: The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base. Registration: URL: https://www.clinicatrials.gov ; Unique identifier: NCT00005134.

Background: The association of circulating trimethylamine‐ N ‐oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results: We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi‐Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow‐up using high‐performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60% (CHS) and 53% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15‐year follow‐up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03–1.18], P =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions: Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.