Primary and Secondary Dyslipidaemia

Question 1

Framingham Heart Study

Answer 1

Identify risk factors that contribute to CVD in those with no history of CVD
Epidemiological approach
Risk factors: high BP, high cholesterol, smoking, obesity, diabetes, physical inactivity

Question 2

Cholesterol Treatment Trialists Collaboration

Answer 2

Controlled trials of lipid intervention therapies

Focused on statin therapy and their efficacy and safety - and therefore reduction of LDL cholesterol

Question 3

Copenhagen City Heart Study

Answer 3

Prevention of CHD and stroke
Describing distribution of known cardiovascular risk factors
Prevalence and incidence of cardio and cerebrovascular disease, hypertension, lung disease and others
Studying genetics, psychosocial factors, arthritis, epilepsy, dementia, excessive alcohol intake and microalbuminuria

Question 4

Risk factors for CVD

Answer 4

Modifiable: smoking, obesity, diabetes, sedentary lifestyle, hypertension, high cholesterol or abnormal blood lipids, excessive alcohol intake
Un-modifiable: age, gender (men), genetic factors/family history, pre-existing CVD

Question 5

Risk Calculator Tools - QRISK3

Answer 5

A large, consolidated database derived from health records
Takes into account many traditional risk factors
Plus additional risk factors (ethnicity, deprivation score, blood pressure treatment, renal failure, BMI, migrane, mental illness…)
A QRISK3 over 10 indicates primary prevention with lipid lowering therapy should be considered

Question 6

Lipid Modification Guideline

Answer 6

Measure full lipid profile
Exclude possible common secondary causes of dyslipidaemia (alcohol, diabetes, hypothyroidism, liver disease, nephrotic syndrome)
Primary and Secondary Prevention: statin (20 mg for primary, 80mg for secondary)

Question 7

Low density Lipoprotein Receptor

Answer 7

LDLR is a cell-surface receptor that recognises ApoB-100 which is embedded in the phospholipid outer layer of LDL particles
Present on most cells but the majority on the liver
LDLR on hepatocytes binds to LDL particles and remove them from the circulation
The LDLR then return to the cell surface to repeat this process

Question 8

Ezetimibe

Answer 8

Potent and selective inhibitor of absorption of cholesterol in the small bowel
The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter
Ezetimibe at 10mg/day has been shown to induce a 20% reduction in LDLC and 8% reduction in TG

Question 9

PCSK9 inhibitors

Answer 9

PCSK9 functions as a binding protein; it is expressed primarily in hepatocytes and after secretion binds to the LDLR and promotes their degradation
By blocking PCSK9, these drugs result in increased availability of LDLR to remove LDLC from circulation
New class of lipid lowering meds
Administered bimonthly subcutaneous injections
Monoclonal antibodies to PCSK9 - developed after observation that naturally occurring loss of function polymorphisms resulting in PCSK9 under expression led to lower LDLC leves

Question 10

Patter of lipoprotein abnormality

Answer 10

Hypercholesterolaemia (raised TC and LDLC)
Mixed hyperlipidaemia (raised TC and LDLC, with raised TG and often low HDLC)
Hypertriglyceridaemia - less common, may be familial tending to cause harm through acute pancreatitis

Question 11

Lipoprotein(a)

Answer 11

Macromolecular complex in plasma
LDL-like +ApoB + Apo(a)
Lipoprotein made by the liver
Association between elevated Lp(a) concentrations and MI, stroke and aortic valve stenosis

Question 12

Apo(a)

Answer 12

Glycoprotein, similar to plasminogen
Unclear physiological function
Pathological function: atherosclerosis and thrombosis formation
Measurement Criteria: intermediate/high risk of CVD; Fhx of premature of CVD/raised LP(a); recurrent CVD despite statin treatment
Treatments: lifestyle changes; 3 effective therapies on controlled trial - Lipid apheresis, PCSK9 inhibitors, antisense therapy

Question 13

Familial Hypercholesterolaemia

Answer 13

Common genetic disorder characterised by increased serum LDL cholesterol and early CVD (autosomal dominant)
Mutations in LDLR gene that encodes LDLR protein
Wide range of age at first cardiovascular event in heterozygous FH
Treatment: low saturated fat diet and exercise, statins, possible addition of cholesterol absorption inhibitor, rarely resins/surgery/LDL apheresis, anti-PCSK9