Arteriosclerosis (Hardening of the Arteries): Causes

Pathogenesis (disease development)

In the following discussion, it should be noted: Atherosclerosis should not be understood as a systemic disease because its expression varies widely and certain anatomic regions (e.g., internal thoracic artery (mammary artery)) are virtually always left out. Small lesions (injury), which can already be present in the arterial wall at a young age, form the symptom-free beginning of atherosclerosis.In the first place, there is endothelial cell damage (so-called endothelial dysfunction; endothelium = cells of the innermost wall layer facing the vessel lumen) due to an increased supply of oxidized LDL, (Low Density Lipoprotein; German: Lipoprotein niederer Dichte) in particular by small, dense LDL particles (“small dense LDL”). The further steps of atherogenesis (development of arterial calcification) are:

  • Attachment of monocytes (belong to the white blood cells; precursors of macrophages, which play an important role in immune defense as “scavenger cells”) and thrombocytes (platelets; blood components important for blood clotting) to the dysfunctional endothelium (cell layer on the inside of blood vessels with disturbed function).
  • Immigration of monocytes and platelets into the intima (innermost layer of the vessel wall)
  • Monocytes become macrophages and ingest LDL particles
  • Macrophages give rise to foam cells (foam-cells), which become lodged in intima and media (middle layer of arteries, depending on the type of vessel, consisting of a more or less distinct muscle layer) and lead to inflammatory reactions (→ fatty streaks; fatty streaks)
  • Endothelial cells and monocytes produce increased cytokines and growth factors (→ proliferation of smooth muscle cells of the media)
  • Migration of smooth muscle cells into the intima and synthesis of collagen and proteoglycans (extracellular matrix; extracellular matrix, intercellular substance, ECM, ECM) leads to the formation of fibrous plaques.
  • Demise of foam cells in the fibrous plaques (→ release of lipids and cholesterol); Ca2+ incorporation results in cholesterol crystals.
  • The media is completely affected by the above process in the final stage and thus loses its elasticity

Particularly dangerous are unstable plaques, the rupture of which can lead to acute vascular occlusion (e.g., myocardial infarction/heart attack). In pathogenesis, the adventitia (tissue surrounding the vessel on the outside) is currently the focus of research. This is useful because it is the only way to understand the differential involvement of individual stromal areas. Another research focus in atherosclerosis research is the investigation of microbiological causes of atherosclerosis. Questions seeking answers are: What causes infection with the vasa vasorum (smallest arteries and veins found in the wall of larger blood vessels) and why are they damaged? Why do localized infections affect vessels far from the focus, such as the aorta (main artery)? How can environmental toxins, infections and other factors trigger the same mechanism of damage? Haverich, director of the Clinic for Cardiothoracic, Transplantation and Vascular Surgery, in Hannover at the MHH, challenges the previous doctrine and argues that the fatty deposits. the so-called plaques, do not come from the blood, but are remnants of dead cells of the vessel wall. He sees this as caused by inflammatory reactions caused by viruses, bacteria and particulate matter, which lead to the occlusion of the vasa vasorum and thus to the death of the tunica media (media; middle wall layer of a vessel/muscle layer). Thus, atherosclerosis of the adventitia (tissue surrounding the vessel to the outside) would run through the outer wall of the arteries into the media and intima. It would thus be a microvascular disease of the adventitia and plaques would be the result of immune system repair processes.Note on this: Oxford University researchers have found that inflammatory responses in blood vessels have effects on perivascular (“around the vessels”) adipose tissue. They measure this using a variant of computed tomography to determine the “fat attenuation index” or FAI. Unlike the coronary calcification index, which indicates the consequence of atherosclerosis, the FAI could detect early damage.A consensus paper of the European Atherosclerosis Society indicates that “low density lipoprotein” (LDL) and other cholesterol-containing lipoproteins are directly involved in the development and progression of atherosclerosis. Furthermore, the authors state that experimentally induced elevation of plasma LDL and other apoB-containing lipoproteins leads to vascular calcification in all mammalian species studied. The fact that LDL cholesterol lowering achieved by medication is proportional to cardiovascular risk argues for causality. Manifestation of peripheral atherosclerosis (modified from).

Region Symptoms
Cerebrovascular arteries Transient ischemic attack (TIA; sudden disturbance of blood flow to the brain leading to neurologic dysfunction that resolves within 24 hours), apoplexy (stroke); unilateral blindness
Upper extremity arteries Subclavian steal syndrome, claudication (progressive stenosis (narrowing) or occlusion (blockage) of the arteries supplying the arms/ (more commonly) legs), digital artery ischemia (reduced blood flow to the finger arteries)
Mesenteric arteries Mesenteric ischemia (reduced supply to blood vessels supplying the intestine), chronic/acute
Renal arteries Secondary arterial hypertension (high blood pressure); renal failure.
Lower extremity arteries Claudication, acute/chronic critical limb ischemia (reduced supply to the limb arteries),

Etiology (causes)

Biographical causes

  • Age of life – increasing age
  • Family history – coronary heart disease (CHD) or myocardial infarction (heart attack) in close relatives (1st degree) – especially if men develop the disease before age 55 or women before age 65, respectively

Behavioral causes

  • Nutrition
    • Malnutrition and overeating, e.g., excessive caloric intake and high-fat diet (high intake of saturated fat).
    • Excessive consumption of red meat, ie. Muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat → increase in biogenic amine TMAO (trimethylamine oxide) by 3-fold; patients with the highest concentrations (top quarter) were 2.5 times more likely to develop myocardial infarction or apoplexy or die in subsequent yearsIndication: Carnitine present in red meat is metabolized in the intestine by bacteria to trimethylamine, which is converted to trimethylamine oxide (TMAO) after absorption in the liver.
    • Sugar-sweetened carbonated beverages (≥ 1,000 ml/week); more frequent coronary calcification (CAC score > 0) on cardiac CT than in comparable individuals who largely avoid soda.
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol (woman: > 40 g/day; man: > 60 g/day) → hypertriglyceridemia (elevated blood triglyceride levels).
    • Tobacco (smoking, secondhand smoke) – Smoking is one of the central risk factors for atherosclerosis and thus for all cardiovascular diseases; secondhand smoke: Children whose parents smoke have an increased risk of developing atherosclerotic plaque in adulthood
  • Drug use
    • Cannabis (hashish and marijuana)? – A long-term study suggests that tobacco smoke, not cannabis use, is the main trigger of atherosclerosis
  • Physical activity
    • Physical inactivity
  • Psycho-social situation
    • Psychological stress
    • Stress
    • Sleep duration ≤ 6 hours vs. 7-8 hours of sleep (+27% increased risk of vascular plaque formation)
  • Overweight (BMI ≥ 25; obesity).
  • Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – there is a high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)); increased abdominal fat has a strong atherogenic effect and promotes inflammatory processes (“inflammatory processes”)When measuring waist circumference according to the International Diabetes Federation guideline (IDF, 2005), 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.For postmenopausal women, waist-to-hip ratio is a better predictor of subclinical atherosclerosis than body mass index or waist circumference

Disease-related causes

  • Arterial hypertension (high blood pressure)
  • Depression
  • Diabetes mellitus (insulin resistance)
  • Hyperlipidemia/dyslipidemia (lipid metabolism disorder) – hypercholesterolemia; hypertriglyceridemia.
  • Hypothyroidism (hypothyroidism) – this is usually accompanied by elevated serum cholesterol levels; latent (subclinical) hypothyroidism is also a risk factor for atherosclerosis
  • Insomnia (sleep disturbances) – sleep fragmentation (arousals) detected by actigraphy (noninvasive method to study human activity and rest cycles) directly and significantly correlated with both cardiac CT calcium score and neutrophil (neutrophilic granulocyte; specialized immune cells belonging to leukocytes (white blood cells)) count. A mediation analysis was able to show that sleep interruptions did not affect the calcium score directly, but mediated by the neutrophil increase.
  • Metabolic syndrome
  • Osteoporosis – significant risk factor for coronary heart disease (CHD): this is explained by the fact that the so-called osteoclasts (bone-degrading cells) – also stimulate sclerosis (calcification) of the arteries.
  • Periodontitis (inflammation of the periodontium).
  • Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation affecting the entire organism), which proceeds without clinical symptoms.

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

  • Apolipoprotein E – genotype 4 (ApoE4).
  • CRP (C-reactive protein) or hs-CRP (high-sensitivity (high-sensitivity) CRP).
  • Cholesterol – total cholesterol, LDL cholesterol, HDL cholesterol.
  • Fibrinogen
  • Hyperhomocysteinemia
  • Lipoprotein (a)
  • Fasting insulin
  • Triglycerides

Environmental pollution – intoxications (poisonings).

  • Air pollutants: particulate matter

Other causes

  • Infections:
    • Chlamydia pneumonia
    • Cytomegalovirus (CMV)
    • Porphyromonas gingivalis (periodontitis germ).
  • Chronic infections – for example, urogenital tract, respiratory tract.

The simultaneous presence of multiple risks/causes potentiates the risk of atherosclerosis.