{"id":550,"date":"2015-01-25T08:00:15","date_gmt":"2015-01-25T08:00:15","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=550"},"modified":"2017-08-21T12:00:24","modified_gmt":"2017-08-21T12:00:24","slug":"primary-care-corner-with-geoffrey-modest-md-hdl-nanoparticles-and-decreased-atherosclerosis-in-mice","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/01\/25\/primary-care-corner-with-geoffrey-modest-md-hdl-nanoparticles-and-decreased-atherosclerosis-in-mice\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: HDL nanoparticles and decreased atherosclerosis in mice"},"content":{"rendered":"

By: Dr. Geoffrey Modest<\/strong><\/p>\n

So, I don’t mean to overdo this HDL thing, but there was a study finding that a synthetic oral\u00a0HDL mimic significantly reduced atherosclerotic plaques in mice (see\u00a0<\/span>DOI\u00a010.1194\/jlr.M049262<\/strong>). Details (in very brief):<\/span><\/div>\n
\u00a0<\/span><\/div>\n
–They created HDL-like nanoparticles (based on multiple apo-A-1 mimetic peptides on a scaffold) and administered them to\u00a0LDL receptor-null mice (a commonly used animal model for atherosclerosis, with a human-like lipoprotein profile) for 10 weeks orally.\u00a0<\/span><\/div>\n
–The oral med was undetectable in the blood, but caused significant reductions in VLDL and\u00a0LDL\u00a0but increases in HDL (perhaps by intestinal effects), and\u00a0<\/span>reduced the development of\u00a0whole aorta atherosclerotic lesions\u00a0by 55% and aortic sinus lesions by 71%<\/b><\/span>. They note that the plasma changes in lipids was these\u00a0apo\u00a0A-1 mimetic peptides were much more than other apo\u00a0A-1 mimetics, which typically do not change cholesterol levels but do decrease atherosclerosis in several animal studies.<\/span><\/div>\n
\u00a0<\/span><\/div>\n
There have been concerns about the efficacy of raising HDL levels in humans, primarily based on studies of\u00a02 CETP inhibitors, where there have been dramatic increases of HDL without clinical benefit. a leading cardiologist editorialized that if another CETP inhibitor does not improve clinical outcomes, we should pretty much abandon HDL as a target of therapy and accept it\u00a0<\/span><\/span>as<\/span><\/span>\u200b\u00a0only\u00a0a marker of cardioprotection. But, as I’ve mentioned several times in prior blogs,\u00a0the issue may be targeting CETP inhibition as a means to increase HDL. Even though there are epidemiologic studies showing that those with genetically lower CETP levels have higher HDL and decreased cardiac mortality, perhaps the drugs we are making to inhibit CETP\u00a0<\/span><\/span>pharmacologically\u00a0<\/span><\/span>are creating dysfunctional and perhaps even pro-inflammatory HDL. For me,\u00a0HDL is conceptually still\u00a0an appealing target for anti-atherosclerotic therapy, given our understanding of the physiology (reverse cholesterol transport and inducing cholesterol efflux from macrophages, as well as\u00a0their anti-inflammatory and anti-oxidant effects).\u00a0There have been a few human studies in the past 2 decades with some intriguing results. in one, they used an IV infusion of apolipoprotein A-1 Milano and phospholipids, where\u00a0apo A-1 Milano is a natural variant found in a small village in Italy where is very little atherosclerosis and\u00a0coupled this\u00a0with\u00a0phospholipid to create\u00a0an HDL mimic\u00a0<\/span><\/span>(see<\/span><\/span>\u00a0Nissen\u00a0SE et\u00a0al.\u00a0JAMA 2003;\u00a0290:2292-300<\/strong>\u200b)<\/span><\/span>. They found that infusing this into\u00a047 patients with coronary atherosclerosis led to a 14.3 mm<\/span><\/span>3<\/sup><\/span><\/span>\u00a0reduction in atheroma volume by intravascular ultrasound, a 4.2% decrease from baseline,<\/span><\/span>\u00a0in only\u00a05 weekly treatments<\/b><\/span><\/span>… I also remember\u00a0<\/span><\/span>a small study done many years ago\u00a0(not sure of reference) which\u00a0found that a\u00a0parenteral\u00a0infusion of HDL itself led to significant decrease in atheroma\u00a0volume\u00a0within 5-6 weeks. the point is: I think the proclaimed death of HDL as a target, even if there is another negative CETP inhibitor study, is premature…. and these poor little mice have reinvigorated this discussion.<\/span><\/div>\n","protected":false},"excerpt":{"rendered":"

HDL nanoparticles and decreased atherosclerosis in mice […]<\/p>\n

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