Dr Prabhu

1. Less commonly considered
atherosclerotic risk factors
Dr Prabhu kumarappan, IVES, Sir Ganga Ram Hospital

2. Less common
causes
Of Atherosclerosis
1. Hyperlipidemia Lp (a) 2. DIET TMAO
3. Infection
A) Virus
B) Bacteria
4. Environmental
toxins
A) Persistent organic
pollutants
B) Heavy metals
C) Air pollution
2 Atherosclerosis – Less common causes
VSI presentations

3. Less common
causes
Of Atherosclerosis
1. Hyperlipidemia
Lp (a) 2. DIET TMAO
3. Infection
A) Virus
B) Bacteria
4. Environmental
toxins
A) Persistent organic
pollutants
B) Heavy metals
C) Air pollution
3 Atherosclerosis – Less common causes
VSI presentations

4. Less common
causes
Of Atherosclerosis
1. Hyperlipidemia
Lp (a)
2. DIET
TMAO
3. Infection
A) Virus
B) Bacteria
4. Environmental
toxins
A) Persistent organic
pollutants
B) Heavy metals
C) Air pollution
4 Atherosclerosis – Less common causes
VSI presentations

5. Less common
causes
Of Atherosclerosis
1. Hyperlipidemia
Lp (a)
2. DIET
TMAO
3. Infection
A) Virus
B) Bacteria
4. Environmental
toxins
A) Persistent organic
pollutants
B) Heavy metals
C) Air pollution
5 Atherosclerosis – Less common causes
VSI presentations

6. Less common
causes
Of Atherosclerosis
1. Hyperlipidemia
Lp (a)
2. DIET
TMAO
3. Infection
A) Virus
B) Bacteria
4. Environmental
toxins
A) Persistent organic
pollutants
B) Heavy metals
C) Air pollution
6 Atherosclerosis – Less common causes
VSI presentations

7. Lp(a)
LDL + Apolipoprotein (a)
Effects: Correlates with primary and secondary
cardiovascular events
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8. Lp(a)
Mechanism of action
PCSK- Proprotein convertase subtilisin/kexin9
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Rx: Statins, Niacin, PCSK9 inhibitors
Apheresis

9. Lp(a) apheresis -
Indications
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Country Recommendation
USA • Homozygous FH: LDL-c ≥ 500 mg/dl (12.9 mmol/L) on maximal possible drug therapy
• Heterozygous FH: LDL-c ≥ 300 mg/dl (7.8 mmol/L) (0–1 additional risk factor), LDL-c ≥ 200 mg/dl (5.2 mmol/L) (≥ 2
additional risk factors or additional high lipoprotein(a)), LDL ≥ 160 mg/dl (4.1 mmol/L) (if at very high risk)
Germany • Homozygous FH
• Severe hypercholesterolaemia (including but not restricted to heterozygous FH): LDL-c elevated on maximal possible drug
therapy (taking the overall risk of the patient into account)
• Lipoprotein(a): progressive CVD (clinically and on imaging) despite optimal control of all other risk factors and lipoprotein(a)
≥ 60 mg/dl
Japan • Homozygous FH
• Heterozygous FH: total cholesterol ≥ 250 mg/dl (6.5 mmol/L) on maximal possible drug therapy
UK • Homozygous FH: LDL-c reduction < 50% on max. drug therapy or LDL-c ≥ 350 mg/dl (9.1 mmol/L)
• Other hypercholesterolaemia (including heterozygous FH): CVD progression and LDL-c ≥ 190 mg/dl (4.9 mmol/L) or lower if
lipoprotein(a) elevated or LDL-c reduction < 40%
Australia • Homozygous FH: LDL-c ≥ 270 mg/dl (7.0 mmol/L) on maximal possible drug therapy
• Heterozygous FH: CVD and LDL-c ≥ 193 mg/dl (5.0 mmol/L) on maximal possible drug therapy
• Alternative criteria (homozygous FH and heterozygous FH): < 50% reduction on maximal possible drug therapy
Spain • Homozygous FH
• Heterozygous FH: LDL-c ≥ 200 mg/dl (5.2 mmol/L) with CVD or ≥ 300 mg/dl (7.8 mmol/L) without CVD

10. Lp(a) apheresis -
Indications
10
Country Recommendation
USA • Homozygous FH: LDL-c ≥ 500 mg/dl (12.9 mmol/L) on maximal possible drug therapy
• Heterozygous FH: LDL-c ≥ 300 mg/dl (7.8 mmol/L) (0–1 additional risk factor), LDL-c ≥ 200 mg/dl (5.2 mmol/L) (≥ 2
additional risk factors or additional high lipoprotein(a)), LDL ≥ 160 mg/dl (4.1 mmol/L) (if at very high risk)
Germany •
Homozygous FH
• Severe hypercholesterolaemia (including but not restricted to heterozygous FH): LDL-c elevated on maximal possible drug
therapy (taking the overall risk of the patient into account)
• Lipoprotein(a): progressive CVD (clinically and on imaging) despite optimal control of all other risk factors and lipoprotein(a)
≥ 60 mg/dl
Japan • Homozygous FH
• Heterozygous FH: total cholesterol ≥ 250 mg/dl (6.5 mmol/L) on maximal possible drug therapy
UK • Homozygous FH: LDL-c reduction < 50% on max. drug therapy or LDL-c ≥ 350 mg/dl (9.1 mmol/L)
• Other hypercholesterolaemia (including heterozygous FH): CVD progression and LDL-c ≥ 190 mg/dl (4.9 mmol/L) or lower if
lipoprotein(a) elevated or LDL-c reduction < 40%
Australia • Homozygous FH: LDL-c ≥ 270 mg/dl (7.0 mmol/L) on maximal possible drug therapy
• Heterozygous FH: CVD and LDL-c ≥ 193 mg/dl (5.0 mmol/L) on maximal possible drug therapy
• Alternative criteria (homozygous FH and heterozygous FH): < 50% reduction on maximal possible drug therapy
Spain • Homozygous FH
• Heterozygous FH: LDL-c ≥ 200 mg/dl (5.2 mmol/L) with CVD
or ≥ 300 mg/dl (7.8 mmol/L) without CVD

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DIET – TMA
(Trimethylamine)  Trimethylamine N-oxide
Derived from “Carnitine” and “Phosphatidyl
choline”
Found in
• Red meat
• Dairy products
• Eggs
Converted to TMA by intestinal bacteria
TMA  TMAO by liver FMO3

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DIET – TMA
(Trimethylamine) 
Trimethylamine N-oxide
Derived from “Carnitine” and “Phosphatidyl
choline”
Found in
• Red meat
• Dairy products
• Eggs
Converted to TMA by
intestinal bacteria
TMA  TMAO by liver
FMO3

13. Trimethylamine-N-Oxide (TMAO) Predicts Cardiovascular Mortality in Peripheral Artery Disease
Roncal, C., Martínez-Aguilar, E., Orbe, J. et al. Trimethylamine-N-Oxide (TMAO) Predicts
Cardiovascular Mortality in Peripheral Artery Disease. Sci Rep 9, 15580 (2019)
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Effects of TMAO:
Increased MACE in patients with CAD, Heart
failure, renal failure
PAD, MI and CAD
PC consumption – Increased
Cardiovascular specific mortality

14. INFECTION
Herpes simplex viruses 1 and 2
Cytomegalovirus
HCV
EBV
Enteroviruses
VIRUSES
Chlamydia pneumoniae
Helicobacter pylori
BACTERIA
Periodontitis:
Porphyromonas gingivalis
ORAL
PATHOGENS
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15. TLR – Toll like receptors
PAMP- Pathogen associated molecular patterns
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Mechanism
Pathogen burden hypothesis
o Activation of innate immune system – Upregulation of
adhesion molecules in vascular endothelium
o TLR’s of Inflammatory cells binds to PAMP’s
o Also binds to oxidised LDL -> Foam cells

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Infection:
No RCT or large prospective cohort trials
proves association of infection and
atherosclerosis
Some Case control studies showed
association with CAD, ischemic stroke, MI
for
• Virulent CAG strains of H.Pylori
• Chlamydia pneumoniae
• Oral pathogens
• HCV
• CMV

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Infection:
No RCT or large prospective cohort trials
proves association of infection and
atherosclerosis
Some Case control studies showed
association with CAD, ischemic stroke, MI
for
• Virulent CAG strains of H.Pylori
• Chlamydia pneumoniae
• Oral pathogens
• HCV
• CMV

18. Environmental toxins
Persistent organic
pollutants
• Herbicides
• Dioxins
• Polychlorinated biphenyls
Source: Metal production, paper mills,
Vietnam war ( Agent orange herbicide)
Heavy metals
• Arsenic
• Cadmium
• Mercury
Air pollution
• Particulates
• Free radicals
• Reactive aldehydes
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Environmental
toxins
Persistent organic pollutants:
Herbicides and Dioxins
Sources: Pulp and paper mills, Metal
production, Industrial waste incineration
Mechanism
1. Binds to AhR ( aryl hydrocarbon
receptors) – Affects cell cycle and
promotes inflammation
2. Upregulation of FMO3
3. Upregulation of inflammatory
mediators by altering intracellular
Calcium ions

20. Heavy metals:
Arsenic
VSI presentations
Atherosclerosis – Less common causes
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Sources:
• Burning of coal
• Waste incineration
• Smelting
• Paper production

21. Drinking water
contamination - Arsenic
o Associated with DM II and HTN even at low
concentration of 50-100 microgram/L in drinking
water
o CAD, Stroke and PAD also linked with exposure of
arsenic
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22. Drinking water
contamination - Arsenic
oAssociated with DM II and
HTN even at low
concentration of 50-100
microgram/L in drinking
water
o CAD, Stroke and PAD also linked with exposure of arsenic
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23. o 40-50% of inhaled and 3-7% ingested cadmium
absorbed in GI tract
o Cadmium-metallothionein-cadmium complex
o Accumulates in Liver, Kidney
o Half life – 4-20 years
CADMIUM
Source: Contaminated vegetables (Greens and
potato), smoke, Water, Tobacco plants
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24. o Increased incidence of MI, stroke, PAD
o Progression of plaque: Increased density of
macrophages in plaque
o Effects: Disruption of endothelial integrity, Increases Free
radical production and depletes scavangers
CADMIUM
Source: Contaminated vegetables (Greens and
potato), smoke, Water, Tobacco plants
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25. Heavy metals:
Mercury
Mercury – Deposits in lakes, oceans as
organic methyl mercury
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• Bioaccumulates in shark, Tuna
• Finnish study: Strong association with MI and
death from CAD

26. Heavy metals:
Mercury
Mercury – Deposits in lakes, oceans as
organic methyl mercury
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• Bioaccumulates in shark, Tuna
• Finnish study: Strong association with MI and
death from CAD

27. Development of DM II
CRP
Prevalence of CAD, IHD and CCF
Air pollution
• Particulates
• Free radicals
• Reactive aldehydes
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28. Mitochondrial dysfunction: a key player in the
pathogenesis of cardiovascular diseases linked to
air pollution
Sri Rahavi Boovarahan and Gino A. Kurian
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Air pollution –
Mechanism
• Systemic inflammation
• Insulin resistance
• Innate immune system activation
through TLR’s
Mitochondrial dysfunction – Free
radical stress
• Increased oxidative stress
• Mutations in mitochondrial
DNA
• Decreasing metabolism

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