334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, and more

KEYPOINTS

• 01

  Atherosclerosis is cholesterol deposited in the artery wall, delivered by apoB particles.

  Dayspring, a lipidologist, calls it 'a dump job': the artery isn't making the cholesterol. Coronary and cerebral arteries matter most because their lumens are pencil-dot small and the tissue is oxygen-hungry. Narrowing usually causes no symptoms until about 75–80% blockage. Plaque rupture triggers clotting that can kill in minutes; Attia notes that close to half of first heart attacks are fatal.

• 02

  The disease starts in childhood and takes decades.

  Autopsy studies show fatty streaks in the aortas of children aged 4–8 and subclinical disease in young soldiers. Fetal studies of mothers with high cholesterol show early lesions. About 50% of men's and 33% of women's first major cardiac events happen before 65. Hence the push for pediatric lipid testing around age 8–9 and 'primordial prevention.'

• 03

  Separate causal risk factors from risk markers.

  Causal: age, smoking, apoB-containing lipoproteins and high blood pressure. Diabetes and kidney disease act largely through dyslipidemia and hypertension, plus other circulating irritants such as homocysteine, ADMA blocking nitric oxide, and uric acid. Markers include calcium scores, hs-CRP and homocysteine. Attia notes that a cause can be neither necessary nor sufficient: smoking raises lung cancer risk enormously, yet about 15% of lung cancer patients never smoked.

• 04

  ApoB counts the particles, and particle number drives entry into the artery wall.

  Each LDL, VLDL, IDL and Lp(a) particle carries exactly one apoB, so the standardised immunoassay is a direct particle count. About 95% are LDL. Once inside, particles stick to proteoglycans, aggregate and oxidise. Monocytes become macrophages and then foam cells (first seen in Anichkov's 1913 cholesterol-fed rabbits). Smooth muscle caps the plaque, and calcium comes late. Smoking, hypertension, high insulin and homocysteine make the endothelium leakier.

• 05

  Insulin resistance shows up in lipoproteins years before glucose rises.

  A 1990s NMR study found big VLDLs, small LDLs and small HDLs in clamp-confirmed insulin resistance, before post-meal insulin, fasting insulin or glucose rose. Dayspring considers insulin resistance and lipoprotein abnormalities inseparable. Attia leans toward some independent harm from hyperinsulinemia, citing diabetes trials where insulin-driven glucose control seemed to damage large vessels.

• 06

  Triglycerides above about 100 mg/dL quietly raise apoB.

  In insulin resistance, the liver makes large apoC-III-laden VLDLs that linger. CETP swaps their triglycerides into LDL and HDL. Lipases then shrink those particles: HDL breaks apart (hence low HDL-C), and small LDLs change apoB shape so LDL receptors clear them poorly. That spreads cholesterol over more particles, which is why LDL-C and apoB disagree. Dayspring calls the 150 mg/dL 'normal' cutoff the 75th percentile and gets nervous above 80–100. His own triglycerides of 102–105 hid a high particle count.

• 07

  Remnants and Lp(a) pack more punch per particle than LDL.

  Lp(a) is an LDL with apo(a) attached, carrying oxidised phospholipids—'gasoline on the fire.' Dayspring says it's about 7–8 times more atherogenic per particle. About 20% inherit it, so test once in life. Remnant VLDLs carry 5–7 times more cholesterol per particle. If apoB looks fine but non-HDL cholesterol (total minus HDL) is high, suspect remnants.

• 08

  HDL cholesterol tells you nothing about HDL function.

  HDL function depends on more than 150 associated proteins and its surface phospholipids, neither measurable clinically. Low HDL-C with disease nearly always comes with high apoB and triglycerides. Very high HDL-C can be dysfunctional. Attia's friend had HDL-C over 100 and LDL-C under 100, yet a high calcium score; he's now on two drugs with apoB at 20–30.

• 09

  Lowering apoB through diet works best through triglycerides and saturated fat.

  Saturated fat signals the liver to make fewer LDL receptors, raising apoB. Dietary cholesterol matters less. Reducing calories and refined carbs lowers triglycerides. Attia reserves drastic fat cuts for people who clearly overeat saturated fat. Fibrates lowered triglycerides in trials but didn't reduce events because they didn't lower apoB—so apoB is the goal.

• 10

  The brain makes all its own cholesterol, and desmosterol may flag over-suppression.

  The brain is the most cholesterol-rich organ, with a half-life of about five years. No plasma lipoprotein crosses into it. In adults, astrocytes make cholesterol via the desmosterol pathway and ship it to neurons on apoE particles; apoE4 versions work worse. Neurons export excess as 24S-hydroxycholesterol. Low serum desmosterol has been associated with cognitive impairment, so Dayspring watches it in E4 carriers on statins.