If you’ve followed the NBT podcast for a while you probably heard Dr. Malcolm Kendrick talking about the tenuous connection between cholesterol levels and cardiovascular disease. Malcolm has published with The International Network of Cholesterol Skeptics on this topic, including a recent review paper entitled LDL-C does not cause cardiovascular disease. In the paper, they include both total cholesterol and LDL-C in their discussions, and if you look at epidemiological data, I think they make a good point. For instance, total cholesterol had almost no effect on mortality in the HUNT-2 study in Norway, and higher levels were associated with lower mortality risk in women. Or the ESCARVAL-RISK study, where higher LDL-C is associated with lower all-cause mortality until it’s well above 200 mg/dl. Or the In-Chianti study, where people over 64 had the lowest mortality rates if they had an LDL-C greater than 130mg/dl. The question then becomes, if not cholesterol, then what? To answer that we must resist monomania and acknowledge the very notion of causation in a complex system is suspicious. Ask not what but how. Malcolm argues in his new book The Clot Thickens that if you maintain metabolic health, manage stress, and mind your endothelial function, cholesterol levels become largely irrelevant. Simple enough, but as you’ll discover in this interview, the devil is in the details. Here’s the outline of this episode with Malcolm Kendrick: [00:00:24] Previous NBT podcasts with Malcolm Kendrick: Why Cholesterol Levels Have No Effect on Cardiovascular Disease (And Things to Think About Instead) and A Statin Nation: Damaging Millions in a Brave New Post-health World. [00:00:42] Book: The Clot Thickens: The enduring mystery of heart disease, by Malcolm Kendrick. [00:03:04] 5-part series with lipidologist Thomas Dayspring (Part 1, 2, 3, 4, 5);  2-hour interview with Ron Krauss on The Drive Podcast. [00:04:23] Book: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. [00:06:12] LDL Cholesterol - challenging mainstream thought. [00:17:16] Fatty streaks never become atherosclerotic plaques; Review: Velican, C., M. Anghelescu, and D. Velican. "Preliminary study on the natural history of cerebral atherosclerosis." Medicine interne 19.2 (1981): 137-145. [00:18:54] Genetic influences; familial hypercholesterolemia (FH) and high clotting factors; Case study of patient with untreated FH but no presence of atherosclerosis: Johnson, Kipp W., Joel T. Dudley, and Jason R. Bobe. "A 72-year-old patient with longstanding, untreated familial hypercholesterolemia but no coronary artery calcification: a case report." Cureus 10.4 (2018). [00:21:22] Clotting factors more important than high LDL; Paper: Ravnskov, Uffe, et al. "Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia." Medical hypotheses 121 (2018): 60-63. [00:25:03] UK Biobank Study: Mora, Samia, Seth S. Martin, and Salim S. Virani. "Cholesterol Insights and Controversies From the UK Biobank Study: Three Take-Home Messages for the Busy Clinician." (2019): 553-555. [00:25:51] Machine learning used to predict cardiovascular disease; Study: Weng, Stephen F., et al. "Can machine-learning improve cardiovascular risk prediction using routine clinical data?." PloS one 12.4 (2017): e0174944. [00:30:54] FOURIER PCSK9-inhibitor study: More deaths in the treatment group; Study: Sabatine, Marc S., et al. "Evolocumab and clinical outcomes in patients with cardiovascular disease." New England Journal of Medicine 376.18 (2017): 1713-1722. [00:31:26] Evolocumab also reduces Lp(a); Study: O’Donoghue, Michelle L., et al. "Lipoprotein (a), PCSK9 inhibition, and cardiovascular risk: insights from the FOURIER trial." Circulation 139.12 (2019): 1483-1492. [00:34:02] APOA-1 Milano and HDL cholesterol. [00:38:45] Lp(a) and Vitamin C, plasminogen and clotting. [00:47: