Coronary Artery Disease: Causes

Pathogenesis (disease development)

The most common cause of coronary artery disease (CAD) is atherosclerosis (arteriosclerosis, hardening of the arteries) of the large coronary vessels. In second place is microangiopathy – narrowing of the small coronary artery branches (small vessel disease). In atherosclerosis, deposits of cholesterol, fatty acids and calcium are formed on the walls of the vessels, resulting in so-called atherosclerotic plaques. These constrict the blood vessel and obstruct the blood flow, so that the supply area can no longer be adequately supplied with oxygen and nutrients (for details on the pathogenesis of atherosclerosis, see the topic of the same name below). Microangiopathy is also a form of atherosclerosis, but it affects the small blood vessels from the arterioles to the capillaries. Diabetics are frequently affected by microangiopathy.

Etiology (Causes)

Biographic causes

Genetic burden (1st-degree relatives): atherosclerosis manifestation in 1st-degree relatives before 55 years of age (men) or before 65 years of age (women); gene regulatory networks (GRNs): 28 GRNs involving between 24 and 841 genes indicate a total genetic contribution to CHD of 32%.
- Genetic risk dependent on gene polymorphisms:
  - Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
    - Genes: APOA2, GUCY1A3, ALPA, MIA3, PARP1, SEZ6L.
    - SNP: rs10455872 in the LPA (lipoprotein (a)) gene.
      - Allele constellation: AG (1.51-fold).
      - Allele constellation: GG (2.57-fold)
    - SNP: rs3798220 in the LPA (lipoprotein (a)) gene.
      - Allele constellation: CT (2-3 fold).
      - Allele constellation: GG (2-3-fold)
    - SNP: rs383830 in an intergenic region.
      - Allele constellation: AT (1.6-fold).
      - Allele constellation: AA (1.9-fold)
    - SNP: rs1333049 in an intergenic region.
      - Allele constellation: CG (1.47-fold).
      - Allele constellation: CC (1.9-fold)
    - SNP: rs688034 in the gene SEZ6L
      - Allele constellation: CT (1.1-fold).
      - Allele constellation: TT (1.6-fold)
    - SNP: rs7250581 in an intergenic region.
      - Allele constellation: GG (1.4-fold).
    - SNP: rs17465637 in the gene MIA3
      - Allele constellation: AC (1.17-fold).
      - Allele constellation: CC (1.34-fold)
    - SNP: rs7692387 in the gene GUCY1A3
      - Allele constellation: GG (1.38-fold) – present in 65% of Caucasians.
    - SNP: rs5082 in the gene APOA2
      - Allele constellation: CC (0.57-fold).
    - SNP: rs1136410 in the gene PAPR1
      - Allele constellation: CC (0.16-fold).
- Genetic diseases
  - Familial hypercholesterolemia (FH; lipid metabolism disorder characterized by elevated blood cholesterol levels) (3.2% of cases; in patients with premature CHD: 6.7%)
Blood group – blood group A
Age – older age (men ≥ 55 y. and women ≥ 65 y.)
Hormonal factors – premature menopause (early menopause; in this case, before age 45) (relative risk 1.50; 95% confidence interval 1.28-1.76)
Socioeconomic factors – low socioeconomic status.

Behavioral causes

Nutrition
- Malnutrition and overeating, viz:
  - Too high calorie intake
  - High-fat diet (high intake of saturated fatty acids, trans fatty acids – found especially in convenience foods, frozen foods, fast foods, snacks – and cholesterol)
  - Low intake of unsaturated fatty acids (monounsaturated and polyunsaturated fatty acids such as omega-3 fatty acids (marine fish)); CHD is also inversely associated with the intake of linoleic acid
  - Too high intake of animal protein, including especially processed meat.
  - Low-fiber diet
  - Low intake of fruits and vegetables
- Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
Consumption of stimulants
- Alcohol – (woman: > 20 g/day; man: > 30 g/day).
- Tobacco (smoking, passive smoking)
Drug use
- Cannabis (hashish and marijuana) (88% more common than among non-users).
- Cocaine
Physical activity
- Lack of physical activity (lack of exercise).
- Intensive physical activity (450 minutes of moderate-intensity physical activity per week) (Whites: 80% higher risk of coronary artery calcification score (CACS > 0).
- Excessive endurance exercise
  - Higher coronary plaque burden
  - Clinically relevant coronary artery calcification (CAC).
Psycho-social situation
- Stress; men who were particularly rapidly stressed as adolescents had a 17% higher risk of CHD in adulthood than those who were found to have high stress tolerance; stress tolerance was determined at the time of muster for military service (age 18 to 19 years)
- Health anxiety: 3% of those without anxiety disorder versus 6.1% with health anxiety (sex-adjusted doubling of risk (hazard ratio, HR 2.12))
- Sleep duration: <5 hours and >9 hours showed significantly worse scores on coronary artery calcium score (CAC) and pulse wave velocity; participants with 7 hours of sleep did best
- Alternating shifts with night duty; nurses who worked alternating shifts with night duty for more than 5 years
- Loneliness and social isolation (29% increased risk (pooled relative risk 1.29; 1.04 to 1.59)
Overweight (BMI ≥ 25; obesity).
- With a body mass index (BMI) of 25 to 29.9 is associated with a 32% increased risk of CHD (still 17% after adjustment for risks from hypertension and hyperlipidemia)
- BMI above 30 is associated with an 81% increased risk of CHD (adjusted for the risks due to hypertension (high blood pressure) and hyperlipidemia (dyslipidemia) still increased by 49%)
Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – high waist circumference or waist-to-hip ratio (waist-to-hip ratio) is present When measuring waist circumference according to the International Diabetes Federation (IDF, 2005) guideline, the following standard values apply:
- Men < 94 cm
- Women < 80 cm
The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men and < 88 cm for women.

Disease-related causes

Arterial hypertension (high blood pressure)
Atherosclerosis
Depression (chronic depression → hypocortisolism/reduced secretion of cortisol → increased inflammation and immune response → favoring progression of CHD).
Diabetes mellitus (insulin resistance).
Fatty liver (steatosis hepatis)
Hyperlipidemia (lipid metabolism disorder) – hypercholesterolemia (LDL-C/correlates, independent of sex, diabetes, body mass index, and other lipidemias, with the occurrences of CHD; HDL-C/inverse correlation between HDL-C levels and the risk of developing CHD), hypertriglyceridemia.
Hypothyroidism (underactive thyroid gland) – this is associated with elevated serum cholesterol levels (hypercholesterolemia)
Idiopathic inflammatory myopathies (inflammatory muscle diseases of unknown cause).
Childhood cancer (5-fold increased risk).
Latent hypothyroidism, especially in patients with moderate to high Framingham risk score
Metabolic syndrome
Renal insufficiency, chronic (renal impairment; 2.3 additional diseases per 1,000 person-years).
Osteoporosis (bone loss)
Periodontitis (inflammation of the periodontium)
Steatosis hepatis (fatty liver)
Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation affecting the whole organism), which proceeds without clinical symptoms.

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

Apolipoprotein E – genotype 4 (ApoE4).
Elevated blood calcium levels: health risk estimation based on Mendelian randomization of defined SNPs: increase in calcium level by 0.5 mg/dl (which is approximately one standard deviation) = 25% increased risk of myocardial infarction, 24% increased risk of coronary heart disease (CHD)
Total testosterone-estradiol ratio – a high testosterone-estradiol ratio is associated with an increased risk of CHD
Cholesterol – patients who have a mild elevation in non-HDL cholesterol levels (≥ 160 mg/d) over a prolonged period of time in early adulthood are at increased risk for coronary artery disease
CRP
Fibrinogen
Hyperhomocysteinemia – increased concentration of the amino acid homocysteine in the blood.
Lipoprotein (a) – for development or progression of a CHD with responsible.
Fasting insulin
Fasting glucose (fasting blood glucose)
- Prediabetes as defined by the American Diabetes Association: 100-125 mg/dl (5.6-6.9 mmol/l) (1.1 times risk)
- Prediabetes according to the WHO definition: 110-125 mg/dl (6.1-6.9 mmol/l) (1.20-fold risk).
Triglycerides

Medication

Aceclofenac, similar to diclofenac and the selective COX-2 inhibitors, is associated with an increased risk of arterial thrombotic events.
ALLHAT trial: doxazosin patients had a higher risk of stroke and combined cardiovascular disease than chlorthalidone patients. The risk of CHD was doubled (Davis et al 2000).

Environmental exposures – intoxications (poisonings).

Noise
- Road noise: 8% increase in risk of CHD for every 10 decibel increase in road traffic noise
- Workplace noise: 15% higher risk of CHD when exposed to noise levels of moderate magnitude (75-85 dB) compared with individuals exposed to noise levels below 75 dB (age-adjusted))
Air pollutants
- Diesel dust
- Particulate matter
Heavy metals (arsenic, cadmium, lead, copper).

Further

Diastolic blood pressure of < 60 mmHg and systolic blood pressure ≥ 120 mmHg (1.5-fold risk; at baseline blood pressure in the ARIC study).