atherosclerosis - risk factors and molecular genetics

see also:

• atherosclerosis and primary prevention;
• pathophysiology of atherosclerosis

• the increase in risk per SD of inflammation measured either by hsCRP (high-sensitivity C-reactive protein) or IL-6 consistently exceeded that of a 1-SD increase in cholesterol or blood pressure

• risk of IHD doubles when average popn cholesterol increases from 5.5mM to 6.5mM
• an increase in 1% in LDL levels in medium term follow up is associated with a 2% increased risk of IHD, whilst in the longer term, there is a 3-4% increased IHD risk
• strength of total cholesterol as a risk factor for IHD falls with increasing age b/n 40-60yrs. after which it remains stable
• HDL-C levels are strongly & inversely correlated with IHD risk in both men & women:
  • 1% descrease is assoc. with 3-5% increase in IHD risk
  • levels < 0.9mM predict increased IHD risk at all TG levels
    • these levels are fequently observed in those with premature IHD with normal total chol.
    • predict future IHD in those with normal total chol. & previous IHD
• ratio of total chol:HDL chol. is the single most powerful predictor of IHD risk
• TG levels are more strongly correlated with IHD risk in women than in men
• apo A-I & apo B may be more powerful predictors of IHD risk than either HDL or LDL alone
• apo E4 allele may be a risk for IHD & for re-stenosis after coronary angioplasty
• high lipoprotein(a) levels appear to be a atherosclerotic cardiovascular disease risk factor including stroke and aortic stenosis
  • concentrations are more than 90% genetically determined and 17% higher in post-menopausal women than in men
  • 1 in 5 people carry a gene variant which causes high lipoprotein(a) levels, esp. those from Africa and less so from south Asia, the Middle East, and Latin America while those from east Asia, Europe, and southeast Asia had the lowest prevalence of this gene ¹⁾
• diet and its affect upon the gut microbiome may have a significant role in hyperlipidaemia, hypertension, diabetes and the development of atherosclerosis²⁾
• see hyperlipidaemia

• continuous, linear association between systolic & diastolic BP and AMI
• overall, HT is associated with 2-3x increase in IHD mortality rates
• LVH:
  • associated with increased risk for AMI and for sudden death
  • NB. echocardiography assessment for LVH shows 7x prevalence than does ECG criteria

• 1 packet/day ⇒ 2x risk of IHD
• long term smoking correlates with severity of atherosclerosis
• also lowers HDL-cholesterol

• synergistic as well as independent risk factor for IHD, atherosclerosis

• parental death from IHD has similar strength of association to IHD risk as does BP, cholesterol & smoking

• BUT strenuous physical activity may trigger plaque rupture!
• regular exercise reduces IHD risk & reduces rate of recurrent AMI

• male:female relative IHD mortality rates/100,000 pop. in Australia in 1995:
  • < 50yrs: 5.1:1; 60yrs: 3:1; 70yrs: 2:1; 80yrs: 1.5:1;

• for each 5yr increase in age, IHD death rates almost double for both men & women:
• male IHD mortality rates/100,000 pop. in Australia in 1995:
  • 60-64yrs: ~400; 70-74yrs: ~1200; 75-79yrs: 2000; 80-84yrs: ~3100; >84yrs: 5000;

• presumably via coronary spasm &/or haemodynamic changes may trigger plaque rupture

• seems each decade of combined oral contraceptive pill (OCP) use results in 20-30% more plaque formation
• see http://www.abc.net.au/science/news/stories/2007/2085475.htm?health

• fibrinogen
• plasminogen activator inhibitor I
• vWf

• dietary vitamin E, flavenoids (eg. red wine) act as anti-oxidants and may be protective for IHD
• dietary omega-3 fatty acids (eg. fish) > 2meals per week reduced IHD by 50% & reduced reinfarction & mortality post-AMI by 30%
• saturated fats and trans-fatty acids increase total cholesterol
• moderate alcohol consumption appears to reduce IHD risk by 20%
• one additional serving of red meat per day increases mortality risk by ~13%
• dietary carnitine (red meat, energy drinks) is converted to TMAO by TMAO-producing bacteria in the gut (vegans do not generally have these bacteria), and TMAO in the blood appears to increase rate of atherosclerosis development
• a large US study published in 2022 suggests eating 1 avocado a week may reduce heart attacks by 16-21% but did not seem to reduce risk of stroke ³⁾
• The Million Veteran Program is a prospective cohort whereby dietary intake of fatty acids was assessed in 158,198 participants that had enrolled between January 2011 and November 2018 and were free of Atherosclerotic cardiovascular diseases (ASCVD) at baseline only showed minimal impacts of changes in levels of dietary fats on development of ASCVD events:⁴⁾
  • if one only looked at Model 3 which adjusted for a wide range of factors, the highest quintile intake participants compared to lowest quintile intakes, the highest hazard ratio was a hazard ratio of 1.11 for conjugated linoleic acid and 1.10 for trans-Monounsaturated fat and interestingly practically nil significant effect for saturated fats, trans-Polyunsaturated fats and cis-Monounsaturated fats while cis-Polyunsaturated fat appeared to be protective with HR of 0.93 although P was 0.07 for the trend.
  • when looking at individual fats:
    • “butyric acid, was associated with having a lower risk of ASCVD” HR 0.92 but only for risks of IHD and ICVD, and not peripheral arterial disease (PAD)
    • “margaric acid were associated with an increased risk of ASCVD” HR 1.12 with “strongest associations with the risk of IHD and PAD, but was not associated with the risk of ICVD”, “Margaric acid is found in trace amounts in dairy and beef fats”
    • “arachidonic acid were associated with an increased risk of ASCVD” however there may have been study issues with this fat
    • higher risks of ASCVD also appeared with higher intakes of trans-vaccenic acid (dairy fat and beef), and palmitoleic acid (cod liver oil, chicken fat, beef fat)
    • most of the other fats did not show statistically significant trends

• 2.3kg weight gain (1 body mass index unit) reduces HDL-cholesterol by 5% as well as increasing levels of LDL & VLDL
• women aged 30-55yrs with BMI >30 had 6.3x risk of HT than BMI < 20
• women who gained 25kg weight since they were 18yrs had 5.2x risk of HT
  • Ref: Ann Int Med 1998 Jan 15; 128: 81-8;
• much of risk is due to associated hyperlipidaemia. hypertension, diabetes, but:
  • abdominal obesity has an independent effect, increasing cardiovascular & all-cause mortality in men
  • in a US Cancer prevention study with 12yr follow up of people excluding: smokers, PH heart disease, stroke, cancer, recent unintentional weight loss, in poor health, died in 1st yr of F/U, or non-white, 62,116 men & 262,019 women were followed up:
    • for each increase of 1 in BMI, CVD mortality over the 12yrs increased by:
      • males: 10% for 30-44yrs old; 3% for 65-74yrs old;
      • females: 8% for 30-44yrs old; 2% for 65-74yrs old;
      • ref: NEJM 1998 Jan 1; 338:1-7.

• a 2025 study suggests that women with uterine fibroids have an almost doubled risk of cardiovascular events over 10 year study period (risk of developing cardiovascular disease was 81% higher among those women with fibroids compared to those without; 5.4% of women with fibroids had experienced a cardiovascular event compared to 3% of women without fibroids). The risk was much higher in women who had fibroids under age 40yrs - the risk for cardiovascular disease was 251% higher (or more than 3.5 times more likely) in those with fibroids compared to those without fibroids. ⁵⁾
• see uterine fibroids (leiomyomas)

• Australian aboriginals & NZ maoris have IHD rates 2.7x national average - for young & middle aged: 10-20x greater
  • due to HT, smoking, diabetes, obesity, excessive alcohol consumption
• Maltese in Australia

• familial hypercholesterolaemia (FH):
  • HZ prevalence 1:500
  • underlies only a small % of IHD
  • > 150 mutant alleles identified (chromosome 19p13.3)
    • ⇒ impaired function of LDL receptor
• familial defective ApoB (FDB):
  • defective binding of apoB to the LDL receptor (chromosome 2q24-p23)
    • ⇒ abnormal clearance of LDL particles
  • not all have high levels of LDL cholesterol & expression of IHD is variable
• type III hyperlipoproteinaemia:
  • apoE2/E2 phenotype (chromosome 19q13) + other abn. (eg. hypothyroidism/diabetes)
    • ⇒ impaired clearance of TG-rich remnant particles via hepatic apoE receptor
      • ⇒ raised cholesterol & TG levels, tendon & palmar xanthomata, peripheral & coronary atherosclerosis (although accounts for small % of IHD)
• familial combined hyperlipidaemia (FCH):
  • probably due to HZ expression of several well-characterised recessive disorders (eg. liporotein lipase defic.)
    • ⇒ small dense LDL particles (“pattern B” LDL), raised apoB, low HDL-C, raised chol. & TG
• homocysteinaemia - 10% of pts with “unexplained” IHD

• ACE gene:
  • ? significance of DD allele
• ApoAI/CIII/AIV cluster:
  • ? significance of these genes - a polymorphism defined by 4 restriction enzymes explained 80% of the excess risk assoc. with FH of IHD in a Scottish study
• glucorticoid receptor polymorphisms:
  • N363S polymorphism (4% of population)
  • A3669G polymorphism

• all biologic processes implicated in pathogenesis of atherosclerosis are likely to have genetic determinants
  • immune system genes:
    • genetic loci implicated in the immune system (CRP, IL1RN, IL6R, IL1F10, IRF1, and NLRP3) and loci associated with metabolic syndrome (APOC1, HNF1, LEPR, GCKR, HNF4A, and PTPN2) consistently associate with elevated CRP levels
    • the IL6R locus itself is detected in genome-wide association studies of coronary artery disease and of calcific aortic valve stenosis (the latter perhaps via lipoprotein(a) levels) ⁶⁾
    • IL6R genetic variant was found to associate not only with coronary and peripheral atherosclerosis as anticipated but was also tightly linked to aneurysm formation in the iliac artery, aorta, and abdomen.
      • atients with giant cell arteritis — a disorder treatable with IL-1R inhibitors — typically develop such aneurysms
  • BP control
  • response of endothelium to shear stress
  • cellular cholesterol homeostasis
  • interactions with the arterial wall
  • lipoprotein oxidation
  • immune responses
  • angiogenesis