We have chosen the top articles supporting the reversibility of atherosclerosis, starting with its pathogenesis and ending with its therapy. There are hundreds of articles on this subject and we will be updating this list periodically when another study is published that furthers our understanding of this subject. If you would like a specific topic or have a specific question concerning atherosclerosis that is not covered by these ten articles, please contact us through the “Contact Page” on this website. We appreciate your interest and efforts in preventing this deadly disease.
1) Question: What new information is available clarifying the pathogenesis of atherosclerosis?
Libby P et al. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004-2013 doi: 10.1056/NEJMra1216063. Click here for full article.
and Libby P. Atherosclerosis: The new view. Sci Am 2002 May;286(5):46-55. Please obtain this article from your library.
Pathogenesis of atherosclerosis – these two publications provide a review of our current understanding of the pathogenesis of atherosclerosis. They emphasize that the lipid hypothesis (that lipid particles such as LDL cholesterol) is part of the culprit in forming the atherosclerotic plaque. They also review the data that inflammation is an equally dangerous participant in the generation of the atherosclerosis plaque and its subsequent rupture into the carotid artery lumen. The two references describe similar data and are redundant but are given because access to them may be different for different individuals. Understanding the pathogenesis of atherosclerosis is essential for initiating its reversal.
2) Question: How important is inflammation is the pathogenesis of atherosclerosis?
Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008(21);359:2195-2207 doi 10.1056/NEJMoa0807646. Click here for full article
Jupiter trial – this clinical trial specifically examined the cardiovascular risk in individuals with elevated hsCRP level (C-reactive protein). Rosuvastatin was used to reduce inflammation. The data indicate that the reduction in atherosclerosis events by the reduction in inflammation was equal to the reduction in LDL cholesterol. It emphasized that atherosclerosis is caused by an approximately equal combination of inflammation and hyperlipidemia.
3) Question: What is a calcium score and how is it measured?
Agatston AS et al. Quantification of coronary artery calcium using ultrafast computed tomography. JACC 1990;15(4):827-832. Click here for abstract
Calcium Scoring – a basic understanding of calcium scoring and what it is measuring is important in the appropriate interpretation of a calcium score. Calcium is deposited in scars throughout the body and atherosclerotic plaques are no exception. Calcium deposition is a late occurrence in all plaques such that early non-calcified plaques can be present when the calcium score is zero. Therefore, even a low calcium score indicates a significant increase in risk. The value of this test to clinicians is paramount to appropriate risk stratification and treatment. It is noninvasive (no contrast agent injected), safe, and inexpensive. It is underutilized by most physicians.
4) Question: What is ezetimibe and how does it work?
Sudhop et al Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans. Circulation. 2002;106:1943-1948. Click here for full article
Cholesterol Blocker - This compound is the only cholesterol intestinal blocker that is FDA approved in the U.S. Its use (10 mg/d) will lower circulation LDL approximately 20% by blocking approximately 50% of free cholesterol absorption in the gut. The majority of free cholesterol in the gut is not from the average American diet (~400 mg/d) but from secretion of the cholesterol by the liver into the hepatic biliary duct (~1500 mg/d) (think cholesterol gall stones). It should be used in conjunction with a statin. It is practically side effect free.
5) Question: What is the optimal goal for the level of LDL cholesterol?
O’Keefe JH, Jr. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43(11):2142-2146 doi: 10.1016/j.jacc.2004.03.046. Click here for full article
How Low should LDL be? The published norms for LDL cholesterol in the U.S. are taken from averages of populations of individuals dying from atherosclerosis. Does this make any sense? This article explains why the norms are much too high for safety. At birth, individual’s LDL cholesterol is in the 40 mg/dl range and only increases when a Westernized diet was consumed. Furthermore, select populations in the world who are “hunter gatherers” have very low LDL cholesterol levels with practically no atherosclerotic heart disease. The same is true of certain genetic variants with low LDL cholesterol levels. This publication is a “must read” article which is critical for reversing atherosclerosis.
6) Question: What are the best predictors of coronary heart disease events?
Budoff MJ et al. Progression of coronary calcium and incident coronary heart disease events (MESA (Multi-ethnic study of atherosclerosis). J Am Coll Cardiol 2013;61:1231-1239.
Mesa outcomes trial – this publication is an observational outcomes clinical trial of an average US community over seven years to identify the most important predictors for atherosclerosis. Of particular note was that the investigators performed calcium scores and internal carotid medial thickness on many of the volunteers. The two most important predictors were age (not a surprise because atherosclerosis is a progressive disease) and calcium scoring (superior to internal carotid medial thickness). This study underscores the importance of performing calcium scoring to quantify risk in most individuals who have not already had a coronary event (they already have a very positive calcium score) and individuals with no risk factors (their score will almost always be zero).
7) Question: At what age is atherosclerosis detectable?
Tuzcu – high prevalence of coronary atherosclerosis in asymptomatic teenagers and adults
Circulation 2001, 103:2705-2710 Click here for full article
Athersclerosis in teenagers - This unique study examined the atherosclerosis in transplanted hearts by ultrasound. Since most of the heart donors were young (automobile accidents), it was an opportunity to assess the earliest stages of cardiac atherosclerosis. Surprisingly, 20 % of teenager hearts had identifiable atherosclerosis and 8o% of individuals aged 20 to 30 years had identifiable atherosclerosis. This study, in agreement with two previous studies, documents that atherosclerosis begins early in life and that it is progressive throughout life.
8) Question: Can atherosclerosis be reversed and at what concentration of LDL cholesterol?
Nissen et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis – the ASTEROID Trial. JAMA 2006;295(13):1556-1565 doi:10.1001/jama.295.13.jpc60002.
Click here for full article
Hiro T et al. Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome. J Am Coll Cardiol 2009;54:293-302. Click here for abstract
Athersclerosis reversability - These two studies are milestones in our understanding of the dynamic nature of atherosclerosis. They demonstrate that atherosclerosis is reversible and provides the level of LDL cholesterol necessary for this biological event to happen.
9) Question: Are statins beneficial in individuals with no history of heart disease?
Brugts JJ, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009;338:b2376
Click here for full article
Colhoun HM. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet 2004;364:685-696. Click here for abstract
Statins and Primary Prevention - The issue of whether statins should be used in individuals with no overt heart disease (primary prevention) but with cardiovascular risk factors is addressed in these two articles. The conclusion is that not only are statins beneficial, but asks the further question as to whether all of these individuals be treated with statins.
10) Question: How beneficial are statins in individuals who have had a cardiovascular event?
Pedersen TR et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453-1460.
Click here for full article.
Statins and Secondary Prevention - Several large, randomized controlled trials have all shown the beneficial effects of statins in individuals with heart disease (secondary prevention). The most famous study is called the 4S study and is cited above. There is now no question that these individuals should be statin treated. The challenge now is to treat them very aggressively with the newer, more potent statins (atorvastatin and Rosuvastatin).
11) Question: Is a higher dose of statin more effective than a lower dose?
LaRosa JC et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-1435. Click here for full article
TNT trial – This publication is a clinical trial comparing both a high dose statin and a low dose statin on the rate of cardiovascular outcomes. The trial was stopped early because the results dramatically demonstrated that the higher dose of statin was much superior to the lower dose. It supports the concept that the lower the LDL the better to prevent atherosclerosis.
12) Question: How does the clinician treat a patient who states that they cannot take a statin?
Meek C et al. Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study. Curr Med Res Opin 2012(Mar);28(3):371-8 doi: 10.1185/03007995.2012.657302.
Click here for abstract.
Joy TR et al. N-of-1 (Single-patient) trials for statin-related myalgia. Ann Intern Med 2014;160(5):201-210 doi: 10.7326/M13-1921. Click here for abstract.
Statin Intolerance - The clinician is often faced with a patient who states that he/she cannot tolerate statin therapy because of muscle aches. Although placebo controlled, blinded clinical trial data indicate that this is a rare phenomenon; patients still attribute multiple aches and pains common in everyday life to statin treatment. The first article provides a simple approach to treating these individuals. The second article documents the rarety of myalgia in patients that are sure they have it.