July 2, 2018

Podcast

Ron Krauss, M.D.: a deep dive into heart disease (EP.03)

"Anybody interested in this field should probably understand the origins." —Ron Krauss

by Peter Attia

Read Time 6 minutes

Whenever I’m stumped on a patient case, or in my thinking about lipids, Dr. Ron Krauss is one of the first people I turn to for insight. I’m not alone. Ron is recognized globally for his research into lipidology and has worn many hats in his career, including clinician, lipidologist, nutrition, genetics, and drug researcher. He received both his undergraduate and medical degrees from Harvard and is board certified in internal medicine, endocrinology, and metabolism. He’s currently the senior scientist and director of atherosclerosis research at Children’s Hospital in Oakland.

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My hope is that both the curious patient and the physician can get a lot out of this episode by being more informed about dyslipidemia and the interventions used to reduce the risk of atherosclerotic disease, cerebrovascular disease, and peripheral vascular disease.

We discuss:

  • The pathogenesis of atherosclerosis;
  • How early atherosclerosis begins;
  • Ron’s motivation for getting into lipidology;
  • How reading an article series in the NEJM in 1967 had a profound impact on him and his career;
  • The “battle” between LDL particle size and particle number;
  • The use of statins;
  • The role of chronic inflammation in atherosclerosis;
  • Why niacin may have been unjustly dismissed as a therapeutic option;
  • The HDL paradox: why drugs that raise HDL-C seem to elevate (or have little impact on) heart disease risk;
  • Mendelian randomization: nature’s randomized trial;
  • How PCSK9 inhibitors work and why they may be underutilized;
  • Lp(a); and
  • More.

Show Notes

“Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease of medium-sized and large arteries fuelled by lipids.” [Falk, 2006] [6:30]

What is the pathology and pathogenesis of atherosclerosis? [7:00]

What is the most common first presentation of heart disease? [10:15]

The different stages of atherosclerosis. [12:20]

When does heart disease begin? [12:40]

What is the biggest risk factor for heart disease? [13:40]

What’s the difference between cholesterol, lipoproteins, LDL-C, LDL-P, and ApoB? [15:40]

One of the greater drivers in the discordance between LDL cholesterol and particle concentration is metabolic syndrome. [25:00]

Does LDL cause heart disease? [30:45]

Taking into account time, and magnitude, of exposure of LDL concentrations. [38:30]

Cholesterol remnants. [42:00]

Ron worked at the NIH with Donald Fredrickson and Robert Levy. [42:45]

As a Med student (Ron had a family history of heart disease), Ron read a series of five articles in the NEJM, that completely transformed him. Ron “made it his business” to come to the NIH and work with Fredrickson, Levy, and Lees after his medical training. [43:30]

Image credit: Wikipedia

Figure. Relative prevalence of familial forms of hyperlipoproteinemia.

Image credit: Wikipedia

Ron wrote a review article on the history of lipoprotein research (Siri-Tarino and Krauss, 2016). [44:45]

“Anybody that’s seriously interested in this field,” Ron said, speaking about lipidology, “should probably understand its origins.” Ron said he received an email after the paper was published, from Joe Goldstein, a Nobel Laureate for his work with cholesterol, who told him that everyone who goes into lipid research should read Ron’s paper.

“The remnants are probably the most pathologic particles of all.” [45:30]

Xanthomas. [46:00]

PCSK9 and PCSK9 inhibitors. [47:00]

Mendelian Randomization. [49:15]

LDL particle size and particle number. [52:00]

Small and very small LDL and how Ron’s testing a hypothesis that these very small particles may be secreted directly (rather than through the VLDL pathway). [1:01:15]

Can LDL-C / LDL-P / ApoB be too low? [1:02:30]

Statins. [1:04:45]

Dementia and desmosterol AUC of the ROC. [Sato et al., 2012; Attia, 2005 for more info on AUC & ROC interpretation] [1:07:30]

Adverse effects of statins (different types of statins may have different side effects). [1:10:45]

Statins and diabetes risk. [1:13:00]

Ron was part of a consensus group on statin side-effects. The first paper came out in 2015 (Stroes et al., 2015) on myopathy, and the second one just came out (Mach et al., 2018), and it describes the data related to diabetes, cognitive function, etc. [1:20:30]

What if statins reduce events, but not by lowering LDL? Maybe the benefits come from the endothelial health and/or inflammatory reduction? [1:24:15]

There was a trial (Ridker et al., 2017) that said we can make no change to the lipoprotein, we can reduce inflammation (in a subset of patients with an elevated CRP, using canakinumab [the CANTOS trial], a therapeutic monoclonal antibody targeting interleukin-1β), and see a lower rate of recurrent cardiovascular events. [1:26:00]

We may or may not see the same thing with methotrexate trial (CIRT trial) results (the study was stopped early, not based on any safety concerns) on the horizon. [CardioBrief, 2017] [1:26:00]

The JUPITER trial analyzed the associated benefit of LDL-lowering against CRP-lowering, a marker of inflammation. A potential double-whammy. Statins may have a unique ability to hit inflammation and LDL metabolism. [1:27:00]

How does Ron rate the strength of the evidence in primary prevention of statins in men and women? MACE and death? [1:29:00]

Statins and cognitive function. [1:33:30]

Statins, muscle effects, and adverse effects on the mitochondria. [1:36:30]

Ron’s involvement with the last ATP panel (ATP IV), a part of the NIH, which handed it off to the American Heart Association and the American College of Cardiology. [Stone et al., 2014] [1:38:00]

Why niacin has fallen out of favor, and why Ron still uses it for patients. [1:40:45]

The HDL-raising effects of niacin are not protective. That’s the conclusion to take away. [1:43:00]

HDL function. [1:45:00]

Does niacin specifically target smaller LDL particles over larger particles? [1:46:30]

Lp(a). [1:47:45]

How statins and PCSK9 inhibitors can widen the discordance between LDL-C and LDL-P, lowering medium- and larger-size LDL particles, and have less of a therapeutic effect on smaller particles, and none on the very small LDL particles. [1:50:00]

Selected Links / Related Material

People Mentioned

Ronald Krauss, M.D.

Ronald M. Krauss, M.D., is the:

  • Senior Scientist and Director of Atherosclerosis Research at Children’s Hospital Oakland Research Institute;
  • Adjunct Professor in the Department of Medicine at UCSF and in the Department of Nutritional Sciences at UC Berkeley; and
  • Guest Senior Scientist in the Department of Genome Sciences of Lawrence Berkeley National Laboratory.

He received his undergraduate and medical degrees from Harvard University with honors and served his internship and residency on the Harvard Medical Service of Boston City Hospital.

He then joined the staff of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, first as Clinical Associate and then as Senior Investigator in the Molecular Disease Branch.

Dr. Krauss is board-certified in internal medicine, endocrinology and metabolism, and is:

  • a member of the American Society for Clinical Investigation;
  • a Fellow of the American Society of Nutrition and the American Heart Association (AHA); and
  • a Distinguished Fellow of the International Atherosclerosis Society.

He’s a member of the U.S. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, founder and past Chair of the AHA Council on Nutrition, Physical Activity, and Metabolism, and a National Spokesperson for the AHA.

Dr. Krauss has also served on both the Committee on Dietary Recommended Intakes for Macronutrients and the Committee on Biomarkers of Chronic Disease of the Institute of Medicine of the National Academy of Sciences.

He has received numerous awards including the AHA Scientific Councils Distinguished Achievement Award and the Centrum Center For Nutrition Science Award of the American Society for Nutrition, and he is listed in Who’s Who in America and the World.

Dr. Krauss is on the editorial boards of a number of journals and is Associate Editor of Obesity.

Dr. Krauss has published nearly 400 research articles and reviews on genetic, dietary, and drug effects on plasma lipoproteins and coronary artery disease.

In recent years Dr. Krauss’ work has focused on interactions of genes with dietary and drug treatments that affect metabolic phenotypes and cardiovascular disease risk. [chori.org]

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.

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