Week 10: Treatments and intervention

Question 1

UK cardiovascular (CVD) disease statistics

Answer 1

• CVD is the UK’s biggest killer (1 in 3 deaths)
• 15% of the population have CVD
• The current cost of CVD to the NHS is over £15 billion per year
• Regional variations exist, largely due to lifestyle choices and differences in standard of living
• 90% of cases, a first heart attack is due to 1 of 9 modifiable risk factors

Question 2

Non-modifiable risk factors for CVD

Answer 2

1. Gender
   * Men have a greater risk of heart attacks than women do and have them earlier in life
2. Age
   * With old age, the prevalence of hypertension increases
3. Genetics
   * Coronary artery disease tends to run in families, not always due to learned behaviour
   * Some forms of cardiovascular disease are more common among certain ethnic groups

Question 3

Modifiable risk factors for CVD

Answer 3

1. Hypertension
   * High blood pressure increases the risk of vessel disease, heart attack and stroke
   * Risk is significantly reduced when blood pressure remains 120/80
2. Diet
   * High saturated fat, sugar and salt diets lead to increased CV risk
   * Mediterranean diets have been shown to protect against CV disease
3. High blood cholesterol (LDL)
   * Cholesterol is carried through the body by lipoproteins: low-density lipoproteins (LDL) and high-density lipoprotein (HDL)
   * High levels of LDL lead to atheroscleoris increasing the risk of CV events
   * HDL reduces the risk of CVD as it carries cholesterol away from the bloodstream
4. Statins
   * Inhibit HMA - CoA reductase - the enzyme responsible for the production of cholesterol in the liver
   * NICE recommend in patients with more than a 10% risk score
   * Can decrease CVD risk by up to 60%
   * Reasonably well tolerated and cheap
5. Smoking
   * Smoking increases heart rate, blood pressure and induces vessel contraction and stiffness.
   * Tobacco also increases clotting activity - thrombus
6. Inactivity
   * Exercise lowers blood pressure, decreases LDL and strengthens heart muscle
   * Overall, CV risk is decreased through exercise, most important factor after (not) smoking
   Summary
   * Exercise lowers blood pressure, drops body fat and serum triglycerides, total cholesterol is lowered as well as LDL’s, HDL’s are increased and as a result of this, so is insulin sensitivity

Question 4

Genome Wide Association Study (GWAS)

Answer 4

• GWAS is an approach to look for genetic variations (SNPs) that are associated with a particular disease
• Researchers compare the genetics of healthy volunteers to people with a disease to look for disease-causing mutations
• There are many worldwide databases that allow the sharing and comparison of screening data

Question 5

Inherited lipid disorders: leptin

Answer 5

• Leptin is a hormone synthesised by fat cells that regulate fat storage
• Acts opposite ghrelin (the hunger hormone) to let the body know when it is full
• Rodents identified with spontaneous mutation in the leptin gene and/or leptin receptor genes leading to uncontrollable hunger and increased fat storage

Question 6

Familial hypercholesterolemia (FH)

Answer 6

• FH is caused by mutations in the genes associated with lipid metabolism
• Autosomal dominant disorder characterised by deficiency or defective function of LDLR
• Affects 1 in 500 people in the UK
• Clinical features: Very high levels of LDL, early onset of CVD
• Symptoms: Yellow cholesterol deposits around eyes and tendons (Xanthomas)
• Around 85% of people with FH are undiagnosed
• Treatment for heterozygotes is statins, the treatment for homozygotes is statins and LDL

Question 7

Prader-Willi Syndrome

Answer 7

• Rare genetic disorder where up to 7 genes on chromosome 15 fail to be expressed correctly
• No single gene defect has been identified
• Severity of symptoms depends on silencing mechanism/severity
• Recent studies have also implicated epigenetics (small nucleolar RNAs)
• Symptoms: growth abnormalities, cognitive impairment and chronic hunger leading to life threatening obesity
  Treatment
• Assisted feeding for infants
• Testosterone therapy for males
• Strict weight control measures
• GH supplementation for children and adults
• Oestrogen therapy for female adolescents
• Genetic counselling

Question 8

Marfan Syndrome

Answer 8

• Autosomal dominant disorder
• 25% of cases are due to de novo mutations
• Caused by an inherited mutation in the fibrillin-1 gene that results in a misfolded protein, unable to bind to TFG-Beta
• This results in an accumulation of TGF-Beta in aorta, heart valves and other tissues
• A similar accumulation of TGF-Beta is observed in Loeys-Dietz Syndrome (LDS) caused by mutations in the TGF-Beta gene
• The location of the amino acid substitutions in the FBN1 protein in different forms of Marfan syndrome
  Marfan Syndrome: aortic pathology
• In Marfan and LDS, the aorta becomes weakened due to the fibrillin-1 defect and TGF accumulation, resulting in an aneurysm.
• The stretching and decreased elasticity may also lead to dissection
• Aortic aneurysms typically have no symptoms
• Aortic dissections cause sudden and severe chest pains and result in massive internal bleeding. Mortality rate is 50-80% upon rupture size
• Once an aneurysm is diagnosed, surgery (endovascular or open) can be performed to prevent rupture
• Anti-hypertensive treatment is also used, sometimes in combination with statins
• Future treatment strategies may include novel drugs, stem cell therapy and CRISPR

Question 9

Long QT Syndrome

Answer 9

• Number of QT causing mutations, mostly in genes encoding potassium, sodium or calcium channels
• The most common, LQT1, is caused by a mutation in the potassium channel, KCNQ1, that is highly expressed in the heart
• Symptoms include dizziness, palpitations, and in some cases, sudden death
• If identified, patients can be treated with drugs or an implantable defibrillator
• A prolonged QT interval can result in torasdes de points which is a form of ventricular tachycardia and can cause sudden cardiac arrest without defibrillation

Question 10

SADS-Brugarda Syndrome

Answer 10

• Sudden death due to ventricular fibrillation
• Most common cause of sudden young adult death in Thai population
• Over 20% of cases due to mutation of the myocyte sodium channel gene SCN5A
• If diagnosed, can be effectively treated with an implanted defibrillator

Question 11

microRNAs in CVD

Answer 11

• microRNAs are short nucleotides (about 22bp in length) and were originally thought to be junk DNA as they are non-coding
• They act as post-transcriptional regulators of gene expression, they can inhibit but not promote translation.
• Recent studies have shown that over 50% of all human genes can be regulated by miRs
• miRs can act as biomarkers for CV disease for detecting risks and also stratifying patients towards the correct treatment approach
• Furthermore, miRs are an attractive target for drug therapy
• Some studies are investigating the potential inhibition of miRs that are associated with CV risk
• Others are aimed at producing ‘mimics’ of miRs that have a positive biological effect

Question 12

miR33a/b

Answer 12

• miR-33a/b have been shown to regulate genes that control cholesterol transport
• Specifically, they repress expression of the cholesterol transported ABCN, which is a key regulator of the HDL biogenesis
• A recent study published in Nature, showed that in animal models, inhibition of miR-33 resulted in a 50% increased in plasma HDL