M103 T3 L17 Flashcards
From what age can atherosclerosis start?
as early as the age 10
What are risk factors for atherosclerosis?
unhealthy lifestyle
obesity
physical inactivity
poor diet
How does atherosclerosis progress?
can become fibrotic
the fibrotic plaques are prone to calcification
it is irreversible at a later stage of life
What complications can fibrotic plaques cause to atherosclerosis patients? (MiSGA)
myocardial infarction
stroke
gangrene
aneurysm
What was the aim of the Framingham heart study (1948)?
to identify risk factors that contribute to CVS disease in a large group of participants living in Framingham, Massachussets, with no history of cardiovascular disease, and they follow them throughout their life
What were two locations of famous heart studies?
Framingham (1948)
Caerphilly (1979)
What did the Framingham and Caerphilly heart studies have in common?
the study was confined to a specific city each time which were well defined and had tough immigration laws
What did the Framingham Heart Study find to be major CVD risk factors?
High blood pressure High blood cholesterol Smoking Obesity Diabetes Physical inactivity blood triglyceride and HDL cholesterol levels age, gender, and psychosocial issues
Why was the Cholesterol Treatment Trialists Collaboration (1994) established?
was set up after it was recognised that no single lipid intervention trial would be likely to have sufficient number of cases, reliably assess mortality outcomes or look at the events in particular type of patients
Which groups of people were involved in the Cholesterol Treatment Trialists Collaboration?
statisticians research scientists cardiologists epidemiologists lipid allergy researchers clinical trialists
What was the aim of the Cholesterol Treatment Trialists Collaboration (1994)?
to conduct periodic meta-analyses of large-scale (≥1000 participants), long-term (≥2 years treatment duaration) unconfounded, randomized controlled trials of lipid intervention therapies
What did the Cholesterol Treatment Trialists Collaboration (1994) investigate?
treatment of high cholesterol and largely focussed on statin therapy and efficacy and safety
What did the Cholesterol Treatment Trialists Collaboration conclude?
a reduction of LDL cholesterol using statin therapy substantially reduces the risk of major CVS events
shows that statin therapy works regardless of age, gender, ethnicity, etc
What is the aim of the Copenhagen City Heart Study?
the prevention of CHD and stroke
What study group does the Copenhagen City Heart Study look at?
a random sample of white men and women aged 20–93 years
How does the Copenhagen City Heart Study collect information?
questionnaires
clinical assessment
biomarkers
What are the two major types of risk factors for CVD?
modifiable (smoking, obesity, diabetes, excess alcoholm hypertension, high cholesterol)
unmodifiable (age, gender, genetics)
What are the functions of the National Institute for Health and Care Excellence?
Provides national guidance advice
provides quality standards and information services for health, public health and social care
containsresources to help maximise use of evidence and guidance
What does the NICE lipid modification guideline CG181 state?
it advises to use key risk risk assessment tool to assess the risk for primary prevention in patients in the general population
Why do we treat lipid disorders that are asymptomatic?
to reduce the atherosclerotic process and the incidence of clinical vascular disease
to prevent pancreatitis which is associated with grossly increased serum triglyceride
What do LDLRs recognise?
ApoB-100 proteins
Where are ApoB-100s present?
they are embedded in the PPLPD outer layer of LDL particles
they are present on most cells but the majority on the liver
How are LDL particles removed from circulation
LDLR on hepatocytes binds to them and removes them from the circulation
the LDLR then return to the cell surface to repeat this process
What is the first line treatment in hypercholesterolaemia and why?
Statins - they inhibit HMGCoA reductase inhibitor so the concentration of cholesterol eventually goes down
How does ezetimibe work?
it’s metabolised into ezetimibe glucuronide
this inhibits the NPC1L1 membrane transporter
reduces biliary cholesterol reabsorption
What is the active metabolite of ezetimibe?
Ezetimibe glucuronide
What is the effect of 10 mg/day of ezetimibe?
20% reduction in LDLC
8% reduction in TG
What is the function of PCSK9 protein?
it controls the number of LDLRs on the surface of hepatocyte by stopping them getting back from inside the cell
it increases the concentration of LDL
What happens when PCSK9 proteins are inhibited / blocked?
there is increased LDLR to remove LDLC from circulation
What medication involves PCSK9 proteins?
PCSK9 inhibitor drugs
How often are PCSK9 inhibitor drugs administered and how?
bimonthly - subcutaneous injections
What observation resulted into research to develop PCSK9 inhibitors?
that naturally occurring loss-of-function polymorphisms caused the under-expression of PCSK9 and led to lower LDLC levels
What are the three main patterns oflipoprotein abnormality?
Hypercholesterolaemia
Mixed hyperlipidaemia
Hypertriglyceridaemia (less common)
What type of patients is Mixed hyperlipidaemia usually seen in?
patients with glucose intolerance
diabetics
What is Mixed hyperlipidaemia caused by?
increased production and reduced breakdown of triglyceride-rich lipoproteins
What are features of Mixed hyperlipidaemia?
raised TC, LDLC and TG
often low HDLC
What is the total cholesterol level in hetero and homozygotic patients with FH?
het- 9 mmol/L
homo- 15–30 mmol/L
What conditions will a patient with Hypertriglyceridaemia usually have?
metabolic syndrome
glucose intolerance
low level of physical activity
poor diet
What is Hypertriglyceridaemia usually caused by?
increased production and reduce breakdown of triglyceride
Which patients might have a very high level of triglycerides
patients with familial conditions
patients who drink excessive amount of alcohol
Which patients might have an isolated raised level of triglycerides in their patient lipid profile?
patients with familial conditions
patients who drink excessive amount of alcohol
patients presenting with new onset diabetes
What does lipoprotein a contain?
a LDL-like particle
ApoB
Apo(a)
What is an increase in Lp(a) concentrations associated with?
myocardial infarction
stroke
aortic valve stenosis
What Lp(a) concentrations show an intermediate or high risk of CVD?
≥3% over 10 years of fatal CVD
>10% over 10 years of fatal and non-fatal CVD
Which conditions are associated with a higher concentration of Lp(a)?
premature CVD, FH recurrent CVD (even with statins)
How is a high Lp(a) concentration in the blood treated?
drugs (approved & investigational) that lower Lp(a)
three effective therapies on continued trial
What are the three effective therapies on trial that have the potential to lower Lp(a) concentration in the blood?
Lipid apheresis
PCSK9i
Antisense therapy
What is the effect of lifestyle changes a on blood Lp(a) concentration?
lifestyle changes have marginal effects on the concentration
What is the statistical effect of lipid apheresis therapy on major CVS event rates?
80-90% reduction
What is the statistical effect of PCSK9i therapy on blood Lp(a) concentration?
reduce levels by 25%
What is the statistical effect of antisense therapy on blood Lp(a) concentration?
can reduce LP(a) levels by up to 90%
What happens during antisense therapy?
small molecules of PCSK9i directly bind to apo(a) mRNA in the nucleus of hepatocytes
What are two disadvantages of LDL-apheresis?
the procedure is very invasive
patients have to get it done often
How is PCSK9i administered?
injections
Has PCSK9i been approved?
no, it is still in trial phase 3 in India
What is the level of Lp(a) that is associated with increased risk of cardiovascular disease?
values of Lp(a) above 300 mg/L
How common is FH?
1 / 200-250 in the UK
Where are the different places the mutations responsible for FH might be?
in theLDLRgene (most common, loss of function)
in the Apo(b) gene (loss of function)
in the PCSK9 gene (gain of function)
At what age does FH usually present in heterozygous patients?
50 year old - male
60 year old - female
How does FH present?
tendon xanthoma
corneal arcus
What is tendon xanthoma caused by?
the accumulation of fat in macrophages in the skin
What age group is corneal arcus uncommon in?
under 40s
How is FH treated?
Low Saturated Fat Diet and exercise
Statins
Possible addition of cholesterol absorption inhibitor (ezetimibe)
Rarely resins/surgery/LDL apheresis
Anti–PCSK9
Involve patient self help group, offer DNA testing and get the family tested.
What does ezetimibe do?
a inhibits cholesterol absorption in the small bowel
When Ezetimibe is absorbed in the SI, what percentage is metabolized into Ezetimibe Glucuronide?
more than 80%
What is the difference between the efficacy of a drug and its active metabolite form?
the active metabolite form has similar effects to those of the parent drug but weaker, although they can still be significant
What membrane transporter is inhibited by ezetimibe glucuronide?
NPC1L1
