Nitric Oxide (NO) is a simple molecule consisting of one atom of nitrogen and one of oxygen, making it even simpler than water. Research into the effects of this small but important molecule began in the 1970’s when scientists started to examine why blood vessels relaxed when certain compounds were added. In 1998, 20-some years after this research first began, a Nobel Prize was awarded to these researchers for their breakthrough discoveries regarding NO. Over the last two decades NO research has continued to grow, and there has been an exponential increase in the number of publications on this fascinating
Many people have the perception that all dietary fat is bad for your health. For years we have been trained and taught by the media, health professionals and even our friends and family that one of the most important things we can do to stay healthy and disease free is to avoid dietary fats. As we get older, often the first warning sign of cardiovascular disease that is flagged by our family doctor is elevated cholesterol. There is little disputing that cholesterol, particularly low density lipoprotein (LDL), has been called the driving force of atherosclerosis.1 However, there is emerging research that challenges the cholesterol hypothesis as the key-driving factor in heart disease. The evidence supporting the cholesterol theory is based on the evidence that high total cholesterol (TC) and LDL are linked to increased numbers of cardiac event endpoints (i.e. a heart attack). Looking at cholesterol levels may be taking the focus away from the disease process really responsible for cardiac events, which is calcified plaque. An accurate and direct way to assess the risk of CHD is the measurement of coronary plaque burden and progression. Assessment of coronary plaque burden via electron beam tomography (EBT) or coronary computed tomography (CT) angiography is a non-invasive measurement of coronary plaque burden. The factor that has been linked to increases in the risk of adverse coronary events is calcified plaque burden.3 More than 10 studies have not found a connection between coronary artery calcification (CAC) progression and TC or LDL levels.4,5,6,7,8 This suggests that cholesterol may not be the key-driving factor in atherosclerosis and cardiac events.8 Based on the above evidence, it seems that cholesterol is not the primary culprit in heart disease. Therefore, lowering cholesterol as the first line of defense for preventing heart attacks and strokes for people with no history of cardiac events should be re-examined. A number of placebo-controlled trials have shown that statin medications do not effect the progression of CAC, despite lowering inflammation and stenosis.9,10 A re-examination of the evidence points to statins not having an impact on all cause mortality in cases where people do not have coronary heart disease.11
It is important to note that statins have demonstrated a protective effect in those that have already experienced a heart attack or stroke. Some of the benefits of statins have been attributed to effects on inflammation or raising vitamin D levels rather than from lowering cholesterol.If elevated TC and LDL have no (or very weak) association with CHD, the unanswered question remains: what is responsible for the high rates of cardiac events and death in North America? What is driving CAC? Consider the fact that the French population eats more fat than any western country (including Canada and the United States), but their incidence of heart-related death is less than half of that in North America. This further suggests that dietary fat is not the main cause of heart disease. The question then becomes, what is it about the standard North American diet, other than the high fat intake, that promotes heart disease? One of the key differentiating factors about the North American diet is that it is high in refined carbohydrates and sugar and low in antioxidant rich foods such as fruits and vegetables. A number of recent papers have solidified the deleterious effects of sugar in promoting diabetes, obesity, and ultimately cardiovascular disease. In 2010, Jakobsen and colleagues showed that replacing saturated fat with carbohydrates further increased the risk of heart attacks while vegetables had a protective effect. Recent evidence suggests that CAC is driven by insulin resistance.12 One of the key factors in the development of insulin resistance is a diet high in refined sugars and carbohydrates. Other factors such as hypertension, stress, depression and sleep apnea have also been linked to increased CAC.13 It is clear that it is time to shift our traditional approaches to preventing and managing cardiovascular disease. There is still merit to lowering cholesterol levels in those with a history of a cardiac event, but for most people the primary focus should not be on lowering cholesterol.8 Interventions that show promise for vascular health are maintaining adequate vitamin D, vitamin K and magnesium levels. The new cardiovascular health approach should emphasize a diet high in antioxidants and fiber, daily physical activity, reducing inflammation, managing stress and maintaining adequate levels of micronutrients, vitamins and essential fatty acids.14
1. Grundy SM. Promise of low-density lipoprotein-lowering therapy for primary and secondary prevention. Circulation. Jan 29;117(4):569-73; 2008.
2. Ravnskov U, McCully KS. Review and Hypothesis: Vulnerable plaque formation from obstruction of Vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009 Winter;39(1):3-16.
3. Church TS, Levine BD, McGuire DK, Lamonte MJ, Fitzgerald SJ, Cheng YJ, Kimball TE, Blair SN, Gibbons LW, Nichaman MZ. Coronary artery calcium score, risk factors, and incident coronary heart disease events. Atherosclerosis. 2007 Jan;190(1):224-31. Epub 2006 Mar 15.
4. Gopal A, Nasir K, Liu ST, Flores FR, Chen L, Budoff MJ. Coronary calcium progression rates with a zero initial score by electron beam tomography. Int J Cardiol. 2007 Apr 25;117(2):227-31. Epub 2006 Jul 26.
5. Hecht HS, Superko HR, Smith LK, McColgan BP. Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment. Am J Cardiol. 2001 Feb 15;87(4):406-12.
6. Kronmal RA, McClelland RL, Detrano R, Shea S, Lima JA, Cushman M, Bild DE, Burke GL. Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation. 2007 May 29;115(21):2722-30. Epub 2007 May 14.
7. Elkeles RS, Godsland IF, Rubens MB, Feher MD, Nugara F, Flather MD. The progress of coronary heart disease in Type 2 diabetes as measured by coronary calcium score from electron beam computed tomography (EBCT): the PREDICT study. Atherosclerosis. 2008 Apr;197(2):777-83. Epub 2007 Oct 24.
8. Ware WR. The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression. Med Hypotheses. 2009 Oct;73(4):596-600. Epub 2009 Jun 26.
9. Henein MY, Owen A Statins moderate coronary stenoses but not coronary calcification: results from meta-analyses. Int J Cardiol. 2011 Nov 17;153(1):31-5. Epub 2010 Sep 16.
10. Houslay ES, et al. Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial. Heart. 2006 Sep;92(9):1207-12. Epub 2006 Jan 31.
11. Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010 Jun 28;170(12):1024-31.
12. Lee KK, Fortmann SP, Fair JM, Iribarren C, Rubin GD, Varady A, Go AS, Quertermous T, Hlatky MA. Insulin resistance independently predicts the progression of coronary artery calcification. Am Heart J. 2009 May;157(5):939-45.
13. Seldenrijk A, Hamer M, Lahiri A, Penninx BW, Steptoe A. Psychological distress, cortisol stress response and subclinical coronary calcification. Psychoneuroendocrinology. 2012 Jan;37(1):48-55. Epub 2011 May 28.
14. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009 Apr 13;169(7):659-69.
Jakobsen MU, Dethlefsen C, Joensen AM, et al. Intake of carbohydrates compared with intake of saturated fatty acids and risk of myocardial infarction: importance of the glycemic index. Am J Clin Nutr 2010 Jun;91(6):1764-8.