Cardiovascular Risk Factors and Testing

Question 1

CVD Causes and RIsk Factors

Answer 1

Family History
Genetics
Ethnicity
Gender

Dyslipidaemia
Hypertension
Mitochondrial dysfunction
Elevated homocysteine
Thyroid hormones
Inflammation
Obesity
Insulin Resistance
Advanced glycation end products (AGEs)
Smoking
Sedentary lifestyle
Chronic Stress
Periodontal disease
Heavy metals
Melatonin deficiency
Gut-brain axis

Question 2

Family History

Answer 2

Siblings of CVD patients = 40% risk increase. Offspring of parents with premature CVD = 60–75% risk increase.

Question 3

Genetics

Answer 3

MnSOD, NOS3, MTHFR and ACE gene polymorphisms

Question 4

Ethnicity

Answer 4

Individualsof South Asian orsub-Saharan African origin have an enhanced risk of CVD.

Question 5

Gender

Answer 5

Common view that CVD is predominantly a male pathology. CVD mortality in women (35–54) is increasing. Risk is underestimated as women tend to experience more vague physical signs e.g., lightheaded with exertion and symptoms can be mistaken for the menopause or heartburn.

Question 6

Dyslipidaema

Answer 6

↑total cholesterol ― ↑ LDL, VLDL, IDL, Lp(a), ↓ HDL; ↑ triglycerides.
– Associated with sedentary lifestyle, excess alcohol, smoking, obesity, high intake of saturated andtrans fat, menopause. Risk increases in T2DM, hypothyroidism and chronic kidney disease. Dyslipidaemia is largely preventable!

Question 7

Hypertension

Answer 7

CVD pathologies tend to appear 5 years earlier in those with hypertension.

Question 8

Mitochondrial dysfunction

Answer 8

ATP is required to pump Ca ions out of myocardial cells, allows relaxation and maintains electrochemical gradient across myocardial cell membrane. Consider statins/CoQ10

Question 9

Elevated homocysteine

Answer 9

Associated with LDL oxidation, monocyte adhesion and ED dysfunction. ↑ levels can relate to:
*Low folate and B12 —needed for the re-methylation of homocysteine to methionine; vitamin B6 —a co-factor in the conversion of homocysteine to cysteine in the methylation cycle.
*Genetic polymorphisms: MTHFR impacts supply of methyl groups needed to methylate B12 in the methionine cycle (in turn methylates homocysteine); FUT2, TCN impact B12 (all forms) absorption. MTR, MTRR impact B12 activation (application of a methyl group).
*The other route for methylating homocysteine is dependent on choline (PEMTand CHDHgenes) and betaine (BHMT gene).

Question 10

Thyroid hormones (TH)

Answer 10

TH receptors are present in the myocardium and vascular tissue and minor TH changes can alter CV homeostasis. Hypo and hyperthyroidism are linked with ED dysfunction, dyslipidaemia and BP changes.

Question 11

Inflammation

Answer 11

Has various origins including dyslipidaemia, dysbiosis and intestinal permeability, ROS, diabetes, excess adipose tissue and smoking. Inflammation contributes to ED dysfunction. In turn, ED dysfunction, subintimal cholesterol accumulation and recruitment of monocytes and T-cells drives the inflammatory response.

Question 12

Obesity

Answer 12

Excessadipose tissue perpetuates inflammation contributing to vascular breakdown and metabolic complications.
* Inflammation is linked with ↑ endothelin-1(ET-1), a potent vasoconstrictorpeptide. Elevated ET-1 leads to fibrosis of VSMCs and ↑ ROS.
* Adiponectin, a peptide that influences expression of ED cells, protecting against CVD, is decreased in obesity.
* Adiponectin also ↑ insulin sensitivity, thus low levels contribute to insulin resistance (IR).
* Obesity is associated with high levels of leptin, which activates the SNS causing sodium retention, vasoconstriction & ↑blood pressure

Question 13

Insulin Resistance

Answer 13

Generates chronic hyperglycaemia leading to oxidative stress, inflammation and cellular damage.
* IR contributes to the lipid triad (high plasma TGs, low HDL, small dense LDLs) and dyslipidaemia.
* Dyslipidaemia along with ED damage (due to dysfunctional insulin signalling) leads to atherosclerotic plaque formation.
* IR means that glucose is not cleared from the bloodstream as quickly as needed, increasing the risk of glycosylation reactions and the production of damaging compounds —advanced glycation end products (AGEs).

Question 14

Advanced glycation end products (AGEs)

Answer 14

Harmful compounds formed when protein or lipids becomes glycated after exposure to glucose.They exert their effects via two main mechanisms:
1. Receptor-mediated: Bind to the cell receptor RAGE (ED, VSMCs and immune cells) increasing inflammatory cytokines and ROS via activation of NADPH oxidase (an enzyme that increases ROS) which activates NF-kB.
2. Non-receptor mediated: Increased EC matrix synthesis, trapping ED LDL and cross binding with collagen (vascular stiffening).
* This leads to oxidative stress, vascular ED and immune cell dysfunction. AGE / RAGE signalling induces fibroblast differentiation and downregulates intracellular detoxifying mechanisms.

Question 15

Smoking

Answer 15

↑oxidative stress (ROS react with NO to form harmful peroxynitrite) and lowers antioxidants (1 cigarette = 25 mg loss of vitamin C). Nicotine over-stimulates SNS and increases BP.

Question 16

Sedentary Lifestyle

Answer 16

Exercise has a positive effect on lipid profile and blood pressure and↑insulin sensitivity and NO production. Brisk walking 30 mins / day can protect against CVD mortality.

Question 17

Chronic Stress

Answer 17

May cause ED dysfunction especially in the presence of other risks e.g., smoking. Activates SNS and HPA-axis, ultimately ↑ inflammatory cytokines. ↑ heart rate and blood pressure through the SNS. Raised activity of the amygdala increases arterial inflammation.

Question 18

Periodontal Disease

Answer 18

—↑ systemic inflammation (↑ TNF, IL-1, IL-6, CRP) which impair vasodilation. Promotes endothelial dysfunction, arterial stiffness and ↑ fibrinogen (plaque formation).

Question 19

Heavy Metals

Answer 19

Induce oxidative stress, lipid peroxidation and inflammatory cytokines. Cadmium and lead compete with zinc. A zinc deficiency increases atherosclerosis risk.

Question 20

Melatonin deficiency

Answer 20

Melatonin is a potent antioxidant with anti-hypertensive properties. It protects against coronary artery disease.

Question 21

Gut-brain axis dysfunction

Answer 21

• SCFAs produced by the microbiota, ↓ risk of metabolic endotoxaemia (a key risk factor for CVD and IR) by maintaining intestinal barrier integrity. SCFAs reduce serum lipids by inhibiting cholesterol synthesis or redirecting lipids to the liver.
• The gut microbiota play a role in cholesterol regulation by altering bile acids that influence systemic cholesterol levels.
• Alterations in the gut microbiota can lead to an increase in harmful metabolites such as trimethylamine-N-oxide (TMAO). TMAO is associated with endothelial dysfunction and increased risk of CVD.

Question 22

Dietary considerations

Answer 22

• High PRAL —foods rich in protein (e.g., meat, cheese) may induce low-grade metabolic acidosis, a risk factor for IR and CVD.
• Trans fats —promote dyslipidaemia (↑LDL-C, TGLs, ↓ HDL-C), increase inflammation, contribute to ED dysfunction, encourage visceral adiposity and increase risk of IR.
• Fructose —high fructose intake promotes de novo lipogenesis, ↑ fatty acids, in particular palmitic acid. Palmitic acid ↑ expression of the receptor involved in the uptake of oxidised LDLs andis a major driver of atherosclerosis and CAD.
• Nutrient deficiencies (e.g., vitamin C, D, E, CoQ10, Mg).

Question 23

Testing

Answer 23

Cardiac Risk Tools
Cardiac troponin
Lipid profile
Lp-PLA 2
hsCRP
MPO

Question 24

Cardiac Risk Tools

Answer 24

QRISK - Calculate score based on CV risks e.g., age, BMI, smoking. QRISK score 10% = 1 in 10 chance of developing CVD in next ten years.

Question 25

Cardiac troponin

Answer 25

Cardiac troponin proteins hs-cTnT and hs-cTnI are released into the blood when heart muscle is damaged e.g., MI. Often measured alongside an ECG (electrocardiogram).

Question 26

Lipid Profile

Answer 26

TC, non-HDL, TG andLDL-C, TC:HDL ratio.
– Normal levels: TC < 5 mmol/L, non-HDL < 4 mmol/L, LDL-C < 3 mmol/L, HDL > 1 mmo /L (men) & > 1.2 mmol/L (women).
–TG > 2.3 mmol/L and TC:HDL > 6 = higher risk for CVD.

Question 27

Lp-PLA 2

Answer 27

Enzyme produced by monocytes, macrophages, T-cells. Upregulated in atherosclerotic plaques and vascular inflammation.

Question 28

hsCRP

Answer 28

Inhibits NO and e-NOS and is involved in plaque deposition. Low risk: < 1.0 mg / L. High risk: > 3.0 mg / L.
* Smoking, a westernised diet, sedentary lifestyle andperiodontal disease elevate both Lp-PLA 2 and hsCRP.

Question 29

MPO

Answer 29

Released by macrophages and measures the body’s response to damaged arterial walls. High MPO isassociated with inflammation / oxidative stress and a poor prognosis. Exacerbated by high BP, obesity and smoking. Low=<470 pmol/L, high ≥ 540 pmol/L.

Question 30

AGEs Risk Factors

Answer 30

• AGEs increase with advancing age. Renal accumulation of AGEs promotes kidney dysfunction.
• Polymorphisms of the AGER gene (encodes RAGE) can ↑disease risk.
• Diet (exogenous AGEs) contribute to overall AGE pool: High refined carbohydrates (sucrose, HFD), processed foods, meatand dairy.
• Cooking methods: High heat, grilling, roasting, searing / frying promote AGE formation.
• Smoking and sedentary lifestyles enhance AGE accumulation.
• Vitamin D appears to ameliorate AGE-mediated complications.