#24 – Tom Dayspring, M.D., FACP, FNLA – Part V of V: Lp(a), inflammation, oxLDL, remnants, and more

KEYPOINTS

• 01

  Lp(a) is an LDL-like particle carrying an extra protein, apo(a), and the name matters.

  Dayspring insists on saying 'little a', because Lp(A) with a capital A would point to apoA-I, the main protein on HDL. Lp(a) is an apoB particle with apolipoprotein(a) attached, and he calls it potentially highly atherogenic. He reminds listeners that it was covered in depth in an earlier episode and gives only a two-minute recap here.

• 02

  Measuring Lp(a) by mass is crude, and particle number is better.

  Most labs report Lp(a) mass, the weight of the whole particle including cholesterol, triglycerides, phospholipids and proteins. Because the molecular weight of apo(a) varies so much between people, Dayspring calls mass a nearly useless metric unless it is very high. A particle count requires separating lipoproteins by electrophoresis and staining the Lp(a) band for apoB, which gives 'Lp(a)-P'. He stresses that this is not an NMR test, and discloses that he works for True Health Diagnostics, which owns the assay.

• 03

  Statins don't lower Lp(a), probably because apo(a) hides the receptor binding site.

  Dayspring thinks LDL receptors are the main way Lp(a) is cleared. Statins increase LDL receptors, but those receptors grab ordinary LDL first, and apo(a) may hide the part of apoB that the receptor binds to. He also notes that Lp(a) levels are driven mainly by how much apo(a) the liver makes, not by clearance. So the real fix is blocking its production.

• 04

  Niacin and PCSK9 inhibitors lower Lp(a), but there is no outcome proof yet.

  Niacin lowers Lp(a) by about 20%, and PCSK9 inhibitors lower it to varying degrees, but insurers won't cover a PCSK9 inhibitor for Lp(a). Any benefit could be credited to lowering LDL and remnants instead. Dayspring doesn't use niacin for this, though he notes Sam Tsimikas does. The decisive test will be an antisense drug from Ionis that blocks apo(a) production, then in phase 3 in high-Lp(a) patients who already had heart disease.

• 05

  Inflammation is 'necessary but not sufficient' for heart disease.

  The anti-IL-1 drug showed fewer events but costs about $30,000 and slightly raised cancer risk, so Dayspring doubts it will ever be approved for routine prevention. Low-dose methotrexate and colchicine trials were still awaiting results. Attia argues that these drugs make sense only for patients whose problem is actually inflammation. Someone with low CRP and fibrinogen whose issue is high LDL particle number wouldn't benefit.

• 06

  The 'oxidized LDL' blood test measures something other than what its name suggests.

  Truly oxidized LDL, the kind macrophages take in to become foam cells, forms inside the artery wall, not in plasma, which is full of antioxidants. The blood test detects aldehydes on apoB, a sign of 'minimally oxidized' particles, usually about 5% of the total. Dayspring uses it, myeloperoxidase (MPO), or preferably urinary F2-isoprostanes to flag a pro-oxidative state and to motivate changes in diet.

• 07

  Dayspring advises against relying on Lp-PLA2.

  The FDA cleared it only for screening in primary prevention. Mendelian randomization shows its levels don't track outcomes, and two large trials that sharply suppressed Lp-PLA2 reduced no events. Attia and Dayspring have both largely stopped using MPO. Attia still finds Lp-PLA2 somewhat informative when Lp(a) is also high, and Dayspring explains why that pairing might matter inside the artery wall.

• 08

  ADMA and SDMA may give a window into endothelial function.

  Both are byproducts of protein breakdown that reduce arginine available for making nitric oxide, so high levels suggest endothelial dysfunction. Dayspring notes that high homocysteine slows ADMA clearance, a plausible mechanism for homocysteine's link to heart disease. He would use these markers to push a borderline primary-prevention patient toward aggressive diet changes, or to justify more apoB lowering in someone already on maximal therapy.

• 09

  Remnants matter, but LDL particles still deliver most of the cholesterol.

  VLDL particles are two to three times larger and carry more cholesterol each. LDL particles vastly outnumber them, though, so most cholesterol entering the artery wall is still LDL-delivered, 'a thousand guys versus one', as Dayspring puts it. Estimates of VLDL cholesterol, from triglycerides divided by five or non-HDL minus LDL cholesterol, often disagree and don't identify true remnants. All approved apoB-lowering drugs clear remnants too.