Jacqueline Krysa | ALES Graduate Seminar

A graduate exam seminar is a presentation of the student’s final research project for their degree.
This is an ALES PhD Final Exam Seminar by Jacqueline Krysa. This seminar is open to the general public to attend.
Thesis Topic: Markers of Non-Fasting Lipids, Remnant Metabolism, and CVD Risk Across the Lifespan
Seminar Abstract: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Increases in circulating lipids (dyslipidemia) is a well-known risk factor for CVD. Traditionally, fasting lipids, inclusive of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC), have been used as lipid risk markers for CVD. However, many individuals, especially those with type 2 diabetes and the metabolic syndrome, still suffer from CVD despite normal LDL-C levels. More recently, non-fasting remnant cholesterol has emerged as a novel CVD lipid risk marker. Non-fasting remnant cholesterol has been found to be causally associated with CVD risk and in some cases has a greater relationship to CVD than traditional fasting parameters. Intestinal remnant cholesterol (measured as plasma apolipoprotein (apo) B48) is significantly elevated in adults with CVD, obesity, and other adverse metabolic conditions. Following a high-fat meal, adults with obesity have an exaggerated and prolonged lipid response in triglycerides (TG) and apoB48, called postprandial dyslipidemia.  The aim of this thesis research was to elucidate the concentration of non-fasting remnant cholesterol in a large Canadian cohort (Alberta’s Tomorrow Project (ATP)) and its association with CVD, measure intestinal apoB48 remnant cholesterol in various clinical populations, and lastly, determine the role of apoB48 remnant cholesterol in early metabolic risk.

Firstly, non-fasting remnant cholesterol was calculated in a Canadian cohort (ATP; n=16,251, average age: 62.32 ± 9.69 years) and the relationship between non-fasting remnant cholesterol and adverse CVD events was determined. It was found that non-fasting remnant cholesterol was significantly elevated in females with prevalence of CVD compared to those without ((0.73 ± 0.36 mmol/L versus 0.83 ± 0.38 mmol/L (12%)) and this was independent of changes in LDL-C. Additionally, we found that increasing quartiles of non-fasting remnant cholesterol positively associated with prevalent and incident CVD case numbers (n=2,936, n=1,169, respectively) whereas LDL-C had no relationship.

Secondly, we compared the fasting and postprandial concentrations of TG, total apoB, and apoB48 in individuals with proprotein convertase subtilisin kexin 9 (PCSK9) – loss of function (LOF) mutations (n=22) compared to those without variants (n=23) following a high-fat meal. PCSK9 is a novel CVD risk marker and individuals with PCSK9-LOF variants have been shown to be protected against CVD. Individuals with PCSK9-LOF had significantly lower fasting TG (-21%) and apoB48 (-26%) compared to non-carrier controls (n=23). LOF variants also had significantly reduced postprandial total-apoB (-17%), apoB48 (-23%), and TG (-18%). The lifelong reductions in postprandial lipids in PCSK9-LOF may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.

The third objective in this thesis was to determine to role of apoB48 remnant cholesterol in early CVD risk. The first part of this objective examined the relationship between fasting apoB48 and cardiometabolic risk factors in 17-year old adolescents from the Western Australian Pregnancy Cohort (Raine) Study (n=1045).  Fasting plasma apoB48 was significantly higher in male (15.28 ± 2.95 ug/mL) compared to female (12.45 ± 2.43 ug/mL) adolescents. Additionally, fasting apoB48 was increased by 21% (3.60 ug/mL) in adolescents in a high-risk metabolic cluster and this increase was more pronounced in males (31%, 6.15 ug/mL). Fasting plasma apoB48 was positively associated with fasting plasma TG, total-cholesterol, insulin, leptin, HOMA-IR, and the anthropometric parameters waist-circumference and skinfold-thickness. Fasting plasma apoB48 was also inversely associated with fasting plasma HDL-C and adiponectin. This study determined that fasting apoB48 remnant lipoprotein concentrations are associated with cardiometabolic risk factors in youth. The second part of objective three aimed to determine the fasting and postprandial lipid response to a high-fat meal in youth with and without obesity. Fasting plasma TG (30%, p=0.03) and apoB48 (55%, p<0.0001) were significantly elevated in obese youth compared to their normal weight peers. Additionally, the postprandial apoB48 (65%, p<0.0001), TG (31%, p=0.005), and TC (20%, p=0.002) response following a high-fat meal was also significantly elevated in youth with obesity.

Overall, the studies in this thesis support the hypothesis that intestinal-derived remnant cholesterol plays an important role in CVD-risk over the lifespan. The above evidence provides a rationale to further implement non-fasting lipid screening measures in Canada and to push towards assessing non-fasting lipids in youth with obesity and other adverse metabolic conditions.

PhD with Drs. Spencer Proctor and Donna Vine