Abstract
Background
Cardiovascular disease (CVD) is a large worldwide medical burden, with yearly increasing morbidity and mortality. An important risk factor for CVD are high cholesterol levels, with low-density lipoprotein cholesterol (LDL-C) as the main focus of research up to now. The introduction of statins has led to a great reduction in LDL-C associated risk and new agents such as ezetimibe and PCSK9 inhibitors are expected to reduce CVD risk even more.
However, even in the case of low LDL-C levels, patients face residual risk. Important risk factors for residual cardiovascular risk are low levels of high-density lipoprotein (HDL) and high levels of triglyceride-rich lipoprotein (TRL).
Aim
This thesis aimed to investigate the relation between genetic causes of (un)favorable lipoprotein profiles, especially with regard to HDL and TRL, and several important clinical endpoints, such as diabetes mellitus (DM) and cardiovascular disease.
Conclusions
The causality between HDL and CVD is debated, which is illustrated by our findings that on the one hand, genetically low HDL was associated with premature CVD in two patients with concurrent HDL-lowering mutations and, on the other hand, we found that the risk of DM and recurrent CVD was not decreased by genetic cholesteryl ester transfer protein (CETP) inhibition in patients with manifest vascular disease, despite increased HDL levels. Further research into HDL and CETP functionality might clarify these contradictions.
Triglycerides (TG) can cause pancreatitis directly, which is shown in this thesis by a case report about a patient with two concurrent TG increasing mutations who was admitted to the intensive care unit for acute pancreatitis. Furthermore, TG are associated with vascular disease via their association with remnant cholesterol. A model disease for remnant cholesterol accumulation is Familial Dysbetalipoproteinemia (FD). The genetic background of FD is a mutation in apolipoprotein E (APOE). The most common genotype associated with FD is the APOE ε2ε2 genotype. This thesis shows that in patients with the ε2ε2 genotype the risk of peripheral artery disease (PAD) is increased and the overall prevalence of CVD in patients with FD is high. The development of FD is associated with secondary risk factors, such as obesity, insulin resistance and metabolic syndrome, that might cause FD through degradation of the heparan sulfate proteoglycan receptor (HSPG-R) by sulfatase 2 (SULF2) upregulation. The treatment target in FD is non-HDL-cholesterol instead of LDL-C. In FD LDL-C should not be estimated with the Friedewald formula, because it overestimates LDL-C in FD. Instead it should be measured with a direct method or gel electrophoresis. Many patients with FD have lipid levels above treatment target. This might be due to inadequate treatment, as this thesis shows thta only 10% gets the recommended combination of statin and fibrate. In patients with type 2 DM the absolute effect of fenofibrate varies widely and it is most effective in patients with a high 5-year risk of major cardiovascular events and/or atherogenic dyslipidemia (high TG, low HDL). In FD addition of a fibrate to standard lipid-lowering therapy results in better post-prandial and fasting lipid levels compared to placebo. These results indicate that, if tolerated, FD patients should be treated with fibrate and statin combination therapy.
Cardiovascular disease (CVD) is a large worldwide medical burden, with yearly increasing morbidity and mortality. An important risk factor for CVD are high cholesterol levels, with low-density lipoprotein cholesterol (LDL-C) as the main focus of research up to now. The introduction of statins has led to a great reduction in LDL-C associated risk and new agents such as ezetimibe and PCSK9 inhibitors are expected to reduce CVD risk even more.
However, even in the case of low LDL-C levels, patients face residual risk. Important risk factors for residual cardiovascular risk are low levels of high-density lipoprotein (HDL) and high levels of triglyceride-rich lipoprotein (TRL).
Aim
This thesis aimed to investigate the relation between genetic causes of (un)favorable lipoprotein profiles, especially with regard to HDL and TRL, and several important clinical endpoints, such as diabetes mellitus (DM) and cardiovascular disease.
Conclusions
The causality between HDL and CVD is debated, which is illustrated by our findings that on the one hand, genetically low HDL was associated with premature CVD in two patients with concurrent HDL-lowering mutations and, on the other hand, we found that the risk of DM and recurrent CVD was not decreased by genetic cholesteryl ester transfer protein (CETP) inhibition in patients with manifest vascular disease, despite increased HDL levels. Further research into HDL and CETP functionality might clarify these contradictions.
Triglycerides (TG) can cause pancreatitis directly, which is shown in this thesis by a case report about a patient with two concurrent TG increasing mutations who was admitted to the intensive care unit for acute pancreatitis. Furthermore, TG are associated with vascular disease via their association with remnant cholesterol. A model disease for remnant cholesterol accumulation is Familial Dysbetalipoproteinemia (FD). The genetic background of FD is a mutation in apolipoprotein E (APOE). The most common genotype associated with FD is the APOE ε2ε2 genotype. This thesis shows that in patients with the ε2ε2 genotype the risk of peripheral artery disease (PAD) is increased and the overall prevalence of CVD in patients with FD is high. The development of FD is associated with secondary risk factors, such as obesity, insulin resistance and metabolic syndrome, that might cause FD through degradation of the heparan sulfate proteoglycan receptor (HSPG-R) by sulfatase 2 (SULF2) upregulation. The treatment target in FD is non-HDL-cholesterol instead of LDL-C. In FD LDL-C should not be estimated with the Friedewald formula, because it overestimates LDL-C in FD. Instead it should be measured with a direct method or gel electrophoresis. Many patients with FD have lipid levels above treatment target. This might be due to inadequate treatment, as this thesis shows thta only 10% gets the recommended combination of statin and fibrate. In patients with type 2 DM the absolute effect of fenofibrate varies widely and it is most effective in patients with a high 5-year risk of major cardiovascular events and/or atherogenic dyslipidemia (high TG, low HDL). In FD addition of a fibrate to standard lipid-lowering therapy results in better post-prandial and fasting lipid levels compared to placebo. These results indicate that, if tolerated, FD patients should be treated with fibrate and statin combination therapy.
Original language | English |
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Awarding Institution |
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Supervisors/Advisors |
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Award date | 13 Apr 2017 |
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Print ISBNs | 978-90-393-6753-7 |
Publication status | Published - 13 Apr 2017 |
Keywords
- cardiovascular disease
- cholesterol
- triglycerides
- high-density lipoprotein
- familial dysbetalipoproteinemia
- type III hyperlipoproteinemia
- apolipoprotein E
- risk
- cholesteryl ester transfer protein