This retrospective cohort study found that higher nonHDLc/HDLc ratio was associated with a higher risk of 30-day mortality in patients with sepsis in the eICU-CRD database from 208 distinct ICUs across the United States between 2014 and 2015. The major finding was that the association between the nonHDLc/HDLc ratio and the risk of all cause mortality was J shaped, with high levels associated with an increased risk of all cause mortality. To our knowledge, this is the first study to report the association between the nonHDLc/HDLc ratio and 28-day mortality in septic patients.
Most studies investigating the relationship between levels of LDLc and the risk of death found no association[18–20] or an inverse association[21–23]. A prospective population-based cohort study with 5 years of follow-up and a validation cohort of African Americans with 4.25-year follow-up show that neither HDLc nor LDLc is associated with mortality. One data from 1948 to 1980 on 5209 men and women enrolled in the Framingham Heart Study found that the negative results in the oldest age group for all-cause morality appeared to be due to a negative relationship with LDL-C levels rather than the protective effect of high HDLc levels. You et al. included 356 patients with intracranial hemorrhage (mean follow-up = 0.22 years) found that the LDLc/HDLc ratio was negatively correlated with all-cause mortality. Liu et al. recruited 3250 stroke patients and found a negative relationship between the LDLc/HDLc ratio and all-cause mortality.
Through observational studies have established that HDLc is inversely associated with both cardiovascular disease and mortality across a wide range of concentrations. A study by Bowe et al. included 1,764,986 men who were US veterans (mean follow-up = 9.1 years) and found a U-shaped relationship between HDL cholesterol and risk of all-cause mortality. A study by Madsen et al. included 116,508 individuals from the general population, the association between HDL cholesterol and all-cause mortality was U shaped, with both extreme high and low HDL cholesterol levels associated with high mortality. No previous study has examined HDLc or LDLc levels associated with the lowest risk of mortality in patients with sepsis. To our knowledge, although the relationship between blood lipids levels and mortality has been concerned, the association between nonHDLc/HDLc ratio and 30-day mortality are still unclear, which prompted us to conduct the current study.
We used non-HDL cholesterol rather than LDL cholesterol because our database measures TC and HDL cholesterol and can be calculated by subtracting non-HDL cholesterol from it. Of the 724 patients included, 178 did not have LDL measurements. In addition, the most commonly used estimation method, the Friedewald equation, can be inaccurate. That non-HDL and LDL cholesterol were correlated in studies with data on both variables (r = 0.93). In our study, the correlation coefficient between non-HDL and LDL cholesterol was 0.92 (95%CI: 0.91–0.94), showing a high correlation. Non-HDL cholesterol predicts CHD risk at least as well as LDL cholesterol because it includes cholesterol in LDL, lipoprotein(a), intermediate-density lipoprotein, very-low-density lipoprotein and lipoprotein remnants, and is thus a simple measure of cholesterol content within all atherogenic lipoproteins.
In addition, a recent study in a Chinese Hypertension Registry study of 6,941 hypertensive patients aged 65 years or older who were not treated with lipid-lowering drugs, during a median follow-up of 1.72 years, 157 all-cause deaths occurred, a U-shaped relationship between the LDLc/HDLc ratio and all-cause mortality was found. This is similar to our result that the mortality rate associated with non-HDLc / HDLc ratios is not liner.
A possible explanation for our findings was that the association between low levels of nonHDLc and an increased risk of all-cause mortality could be explained by reverse causation. Debilitation and illness are hypothesized to cause a decrease in levels of cholesterol[31, 32]. Nonetheless, cholesterol-related risks are more complex and involve the interplay of several factors such as cholesterol particle concentration, reverse cholesterol transport, and triglyceride-rich lipoproteins, to mention a few. The J shaped association between nonHDLc/HDLc ratios and mortality may resemble the obesity paradox, which is largely explained by methodological issues, including reverse causation.
The current retrospective cohort study is based on the eICU-CRD database and may be important for understanding nonHDLc/HDLc ratios in septic patients (ie, when the focus is not limited to myocardial infarction or atherosclerotic cardiovascular disease). We investigated thresholds for nonHDLc/HDLc ratio levels that significantly increased the risk of death in patients with sepsis.
One limitation of this study is inherent to the observational nature of the study design, which lends itself subject to limitations that should be considered including confounding by indication. Our findings are hypothesis-generating and do not imply causality. In our analysis, we adjusted for possible confounding factors, including age (years), gender, weight, heart rate, SOFA score, and site of infection. Despite this adjustment, some unmeasured confounding may remain. Additional limitations of our study include missing data for some variables. Nonetheless, we used contemporary methods to deal with missing data to minimize bias.
Another limitation is related to the fact that the diagnosis was based on the ICD-9 coding which the responsible physician found relevant, and we did not have information concerning causes of death. Since we are examining mortality over a short period after the date of visit to the ICU, we did not find it beneficial to distinguish between cardiovascular and non-cardiovascular death.
Furthermore, lack of information on interventions during the initial stabilization may have influenced nonHDLc/HDLc ratio levels and survival. It is noteworthy that the potential resulting from interventions would bias toward to the null, and thus result in an underestimation of the association between nonHDLc/HDLc ratio level and mortality.
Finally, we acknowledge that the participants were patients referred to the emergency department for some reason, limiting the generalization of findings to other populations.