Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Sex specific associations of ceramides with cardiopulmonary fitness in the general population

J. Zatloukal1, M. R. P. Markus1, R. Ewert2, S. Gläser3, N. Friedrich4, H. Völzke5, S. B. Felix1, M. Dörr1, M. Bahls1, S. Groß1

1Klinik & Poliklinik für Innere Medizin B / DZHK Standort Greifswald, Universitätsmedizin Greifswald, Greifswald; 2Klinik und Poliklinik für Innere Medizin B, Universitätsmedizin Greifswald, Greifswald; 3Klinik für Innere Medizin - Pneumologie, Vivantes Klinikum Spandau, Berlin; 4Institut für klinische Chemie u. Laboratoriumsmedizin, Universitätsmedizin Greifswald, Greifswald; 5Institut für Community Medicine - Abt. SHIP-KEF / DZHK Standort Greifswald, Universitätsmedizin Greifswald, Greifswald;

Introduction According to the WHO 17.9 million people die because of cardiovascular diseases (CVD) each year, being the 3rd leading cause of death worldwide. A high level of cardiorespiratory fitness (CRF) is an important protective factor against cardiovascular events and mortality. Whereas, long-chain unsaturated ceramides like C16:0 have been related with cardiac events, heart failure and all-cause-mortality. However, not all ceramides are equal. We previously showed potential beneficial effects of very-long-chain ceramides (e.g. C24:0) with higher concentrations being inversely associated with cardiovascular events. Whether the beneficial effects of higher CRF are potentially mediated by ceramides is currently unclear. Purpose We explored the association of three specific ceramides (C16:0, C22:0 and C24:0) and their ratios with different parameters of CRF in the general population. Methods We used data of the population-based Study of Health in Pomerania (SHIP-1) from North-East Germany (N: 1,247/men: n=583, median age: 50.0 years/women: n=664, median age: 50.5 years). Ceramides were assessed by LC/MS assay. CRF was assessed during symptom-limited cardiopulmonary exercise testing on a bicycle ergometer. VO2peak, VO2@AT, Wattmax and respective indexing per "kg body weight" were used as outcome. Sex-stratified linear regression models adjusted for age, smoking, body mass index, waist circumference and diabetes mellitus were used. Participants with asthma, chronic lung disease, LVEF < 40% and cancer were excluded from analyses. Results In males, a 1-unit higher C24:0/C16:0 ratio was associated with higher VO2peak/kg, greater Wmax and Wmax/kg. In addition, in men a 1 µg/ml higher C24:0 concentration was related to greater Wmax/kg (Table 1). In females, a 1-unit greater C24:0/C16:0 ratio was associated with greater VO2peak, VO2peak/kg, higher VO2@AT/kg as well as greater Wmax/kg. Furthermore, in women a 1 µg/ml higher C16:0 concentration was related to smaller Wmax and Wmax/kg (Table 1). Table 1: Significant effect estimates for associations of plasma ceramides (1-unit change) with CRF parameters  CRF parameter  estimate 95% confidence interval p-value  Males:        Cer(24:0/16:0)        VO2peak/kg  0.199 ml/min/kg  0.032;0.365  0.019  Wmax  1.368 W  0.033;2.404  0.010  Wmax/kg  0.018 W/kg  0.007;0.029  0.002  Cer(24:0)        Wmax/kg  0.054 W/kg  0.009;0.099  0.018  Females:        Cer(24:0/16)        VO2peak  8.603 ml/min  0.019;17.013  0.045  VO2peak/kg  0.186 ml/min/kg  0.054;0.319  0.006  VO2@AT/kg  0.136 ml/min/kg  0.040;0.231  0.005  Wmax/kg  0.015 W/kg  0.004;0.026  0.007  Cer(16:0)        Wmax  -55.447 W  -101.775;-9.119  0.019  Wmax/kg  -0.736 W/kg  -1.0341;-0.130  0.017 Conclusions We report sex-specific associations between ceramides and CRF. In females, more CRF parameters were positively related with Cer(24:0/16:0) than in men. Furthermore, both sexes differed from each other regarding the single ceramides, a positive relation of C24:0 with CRF in men and an inverse association of C16:0 in females. Thus, C24:0 is related to greater CRF, whereas C16:0 is connected with smaller CRF. This finding agrees with previous reports that C24:0 is beneficial, whereas C16:0 is associated with a higher risk for cardiovascular events. Future studies should explore the reason for the different sex ceramide profiles and whether ceramides are causally contributing to the beneficial effects of high CRF on cardiovascular outcomes.

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