CHOLESTEROL (and other cardiovascular risk markers)
What is Cholesterol and what are its functions?
Cholesterol is a waxy, fat-like substance that is present in all animals, but not in plants (phytosterols are present in plants instead).
Every cell in our body contains cholesterol; we cannot live without it.
Cholesterol is a vital component of cell membranes.
Plays a key role in membrane fluidity, thus influencing transmembrane signaling.
According to the Weston Price Foundation, it is a potent antioxidant that protects against free radical damage to the cell membrane.
Cholesterol is also in many of the cellular organelles.
Cholesterol in the brain promotes myelin formation (insulates neurons) and neuronal plasticity (Prog Neurobiol. 2006. 80. 165-176).
Cholesterol is the biochemical precursor to all steroid hormones, vitamin D, and bile acids.
93% of cholesterol in the body is found in the cells of the body, 7% in the blood.
Cholesterol alone is not very soluble in blood, so it is carried in the bloodstream by molecules called lipoproteins.
Lipoproteins are named based on their density.
We know from the careful study of cholesterol metabolism that high density lipoprotein (HDL) is "good" - it transports cholesterol to the liver.
Low density lipoprotein (LDL) is "bad" - oxidized LDL gets deposited in the walls of arteries, contributing to arteriosclerosis.
What is the source of cholesterol in the blood?
The liver makes cholesterol.
In general, the higher the saturated fat content of the diet, the more cholesterol made by the liver.
Approximately 80% of total body cholesterol is synthesized in the liver – we typically consume 200-300 mg daily of cholesterol, and the liver typically synthesizes 800 mg daily of cholesterol.
Most cells can make cholesterol – high insulin levels signal cells to synthesize cholesterol instead of taking up cholesterol from the bloodstream.
The cholesterol in the food we eat contributes little to the blood cholesterol level. Current average cholesterol intake estimated at 430 mg/day, prehistoric intake estimated at 520 mg/day.
Why is the blood cholesterol level important?
Consistent evidence links increased cholesterol levels to an increased risk of coronary heart disease (CHD)
Data gathered in The Seven Countries Study linked blood cholesterol levels to coronary mortality (Keys A, et al. Acta Med Scand. 1966. 460 [suppl]. 1-392).
Japanese who moved to Hawaii and San Francisco had higher blood cholesterol levels and coronary event rates than Japanese who did not migrate (Am J Cardiol. 1977. 39. 239-243).
Epidemiologic data from the Framingham study confirms the link between cholesterol levels and CHD risk (Ann Epidemiol. 1992. 2. 23-28).
Data from the ARIC study, a prospective study with 15 year follow up, shows that a that each 1% increment in LDL is associated with a 2-3% increment in cardiovascular risk (N EnglJ Med. 2006.354. 1264-1272 and 1310-1312)
A long-term outcome study in 3277 healthy Finnish businessmen aged 30-45 at baseline who were followed for 39 years found that above a total cholesterol of 5 mmol/L (194 mg/dl), higher total cholesterol was associated with a higher total mortality and a worse physical quality of life, as assessed by the RAND-36 questionnaire (J Am Coll Cardiol. 2004. 44. 1002-1008, as abstracted in Cardiology Review. 2006. 23 (1). 13-16).
Note: For reasons that are not yet understood, population studies show that the blood cholesterol level in people over age 70 is not correlated very strongly with the risk of heart attack (JAMA. 1994. 272. 1335-1340).
Note: The total cholesterol level in the blood is not as important as the ratio of total cholesterol (TC) to HDL cholesterol.
Recent data indicate that this ratio predicts the risk of heart attack independent of the level of LDL cholesterol in the blood (Ann Intern Med. 1994. 121. 641-647).
The higher the ratio of TC: HDL, the higher the statistical risk of plaque building up on the walls of the coronary arteries which supply the heart with blood.
Note that despite convincing evidence from clinical trials that statins reduce the risk of stroke, the data from epidemiologic trials with regard to the relationship between serum cholesterol and stroke risk is mixed (Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995. 346. 1647-1653).
What are the other risk factors for heart attacks?
The level of triglycerides in the blood stream - the statistical correlation between blood triglyceride level and heart attack risk is not as strong as the statistical correlation between the blood cholesterol level and heart attack risk.
High blood pressure.
Family history (defined as a male relative with a heart attack under age 55 or a female relative with a heart attack under age 65).
What is a “good” blood cholesterol level?
In general, the lower the better, at least down to a cholesterol level of 140.
The normal LDL cholesterol amongst hunter-gatherers, healthy human neonates, and free living primates is 50-70 (J Am Coll Cardiol. 2004. 43. 2142-2146).
For total cholesterol, the upper limit of normal used to be defined arbitrarily as the level two standard deviations above the average cholesterol level for Americans - approximately 360 on most lab reports.
Based on this definition, only 5% of the population had an abnormal cholesterol level.
In the 1980's, as researchers learned more about the dangers of high cholesterol levels, the upper limit of normal was arbitrarily redefined as 200 on most lab reports.
HDL should be greater than 35 - this can be measured along with total cholesterol in a nonfasting state.
LDL should be less than 130 - a valid measurement requires a 12 hour fast.
In diabetics, or in people with a previous history of heart attack, stroke, or peripheral vascular disease, LDL should be less than 100.
Triglycerides should be less than 150 - a valid measurement requires a 12 hour fast.
Note on terminology and pathophysiology - there is only one type of cholesterol in the diet, but in the blood cholesterol is carried by proteins and these are called lipoproteins and HDL refers to high density lipoprotein and LDL refers to low density lipoprotein. We know that HDL carries cholesterol back to the liver whereas LDL deposits cholesterol in the walls of arteries.
What are the benefits of lowering the blood cholesterol level?
Current data in aggregate indicates that at least in middle aged men, lowering LDL cholesterol by 1% (either by lifestyle changes or medications) decreases coronary events by approximately 1%.
Note that early intervention trials to reduce coronary events by lowering blood cholesterol levels yielded mixed results (Steinberg D. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (J Lipid Res. 2005. 46. 179-190), such that at least one review concluded in 1992 that “lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease” (BMJ. 1992. 305. 15-19).
One early positive trial was the Lipid Research Clinics Primary Prevention Trial in which 3806 asymptomatic middle aged men with hypercholesterolemia were randomized to placebo or cholestyramine and followed for a mean of 7.4 years, a 13% greater reduction in LDL was associated with a 19% reduction in the primary end point, a composite of cardiac death or MI (JAMA. 1984. 251. 351-364).
The statin trials, the first of which was published in 1994 (4S Trial), in aggregate have shown conclusively that lowering serum cholesterol reduces not just cardiovascular mortality, but also total mortality, at least in secondary prevention trials.
What are the risks associated with lowering the cholesterol level?
A scientific statistical meta-analysis of six major primary prevention trials (BMJ. 1993. 306. 1367-1373) shows that the 15% decrease in deaths from heart disease in the cholesterol lowering treatment groups is offset by increases in deaths from gallbladder disease, cancer, and injuries.
The cause of this recurrent finding of increased noncardiac death rates in patients on cholesterol lowering medication is unclear, but it suggests that in young, otherwise healthy adults, the risks of medication treatment for high cholesterol may outweigh the benefits.
Noncardiovascular mortality was NOT statistically significantly increased in any of the large statin trials.
There is some animal data indicating that some cholesterol lowering drugs (fibric acid derivatives such as Lopid and Atromid, and possibly the HMG CoA reductase inhibitors) may cause cancer.
Anecdotally, lowering cholesterol can cause memory impairment.
There does not seem to be a risk of lowering cholesterol by lifestyle changes; the risk seems to be seen only when medications are used.
Should a high cholesterol level be lowered in seniors (>age 65) without known atherosclerosis?
This is controversial – from a statistical standpoint elevated cholesterol in seniors is not as strong a predictor of heart disease as elevated cholesterol in middle aged individuals.
Anecdotally, lowering cholesterol in seniors may cause memory impairment.
There is statistical data that low cholesterol levels in seniors is associated with increased all-cause mortality, with a prospective study of 2277 individuals showing that this association is independent of comorbid illnesses (J Am Geriatr Soc. 2005. 53. 219-226).
How often should the blood cholesterol level be measured?
The National Cholesterol Education Project (NCEP) and some other authorities call for measuring a blood cholesterol level for screening purposes in all adults over age 20, every 5 years.
The United States Preventative Services Task Force (USPSTF) and the American College of Physicians (ACP) currently recommend every 5 year screening only in males over age 35 and females over age 45, in the absence of other risk factors for heart disease (see the list above).
The basis of this recommendation is data which suggests that most of the cardiovascular risk associated with a high cholesterol can be reversed within two years of starting treatment in a middle aged, high risk population.
Note: Policy documents formulated by groups consisting mostly of clinical epidemiologists (USPSTF) recommend initiation of screening at a later age than documents formulated by groups consisting mostly of lipid specialists NCEP).
Anytime cholesterol is measured for screening purposes, HDL should also be measured.
It is debatable as to whether screening cholesterol levels should be measured in adults over age 70, since the statistical correlation between cholesterol levels and heart disease risk is either very weak or non existent after age 70.
If the total cholesterol is over 240 in an adult without other risk factors for heart disease, or is over 200 in an adult with at least two other risk factors for heart disease, NCEP recommends repeating screening cholesterol levels every year.
Cholesterol should be rechecked after 6-8 weeks in somebody on treatment (either lifestyle changes or medications).
NOTE, based on data in 4162 subjects in the PROVE-IT-TIMI 22 Study, there is evidence of seasonal variation in LDL and HDL levels in individuals on statin medications, with LDL statistically significantly lower in the summer than the winter (magnitude 4-6 mg/dl) and HDL statistically significantly higher in the summer than the winter (magnitude 1-2 mg/dl) [Am J Cardiol. 2009. 103. 1056-1060].
How can one improve ones cholesterol: HDL cholesterol ratio?
Alcohol - 1-2 drinks per day raises HDL cholesterol as much as 9-13 mg/dL (Am Heart J. 2004. 147. S29-S35; Am J Clin Nutr. 2002. 75. 593-599).
Consistent aerobic exercise lowers the cholesterol: HDL cholesterol ratio by 15% (Circulation. 1995. 92. 773-777).
A meta-analysis of 25 RCTs shows that (1) a minimum exercise volume of 120 minutes of exercise per week or 900 kcal of energy expenditure per week is necessary to raise HDL, (2) mean net change in HDL is statistically significant but moderate at 2.53 mg/dl, (3) exercise duration per session seems to be the most important factor in determining the effect of aerobic exercise on HDL levels, with every 10 minute prolongation of exercise per session associated with a 1.4 mg/dl increase in HDL, and (4) exercise is most effective in individuals who at baseline have total cholesterol of >220 mg/dl or a BMI < 28 (Arch Intern Med. 2007. 167. 999-1008).
Optimism is associated with a healthier lipid profile, based on data in 990 adults in the Midlife in the United States Study. Some of the association of optimism with healthier lipid profile is attributable to the association of optimism with healthier lifestyle. However, optimism is associated with a higher HDL and a lower triglyceride level, independently, after adjustment for covariates (Am J Med. 2013. 111. 1425-1431).
Relaxation techniques (meditation, yoga) lower cholesterol and LDL cholesterol.
Smoking cessation lowers cholesterol and LDL cholesterol, and raises HDL cholesterol.
Ultraviolet light (i.e. sunlight) -in one experiment, 97% of subjects experienced a 13% decrease in serum cholesterol two hours after exposure to ultraviolet light, and 86% maintained the drop in cholesterol 24 hours later (Circulation. 1953. 8. 438).
Weight loss raises HDL cholesterol.
Replacing trans fats with polyunsaturated fats from unhydrogenated oils is the most effective dietary measure for improving lipid profiles, based on a meat-analysis of 60 controlled trials (Am J Clin Nutr. 2003. 77. 1146-1155).
A diet low in saturated fat lowers cholesterol and LDL cholesterol.
Studies show that a population based educational approach is associated with a 1-11% reduction in cholesterol levels.
Other studies show that an individual counseling approach is associated with a 5-14% reduction in cholesterol levels (75-80% of the reduction seen in "metabolic ward studies" in which the individual is in a controlled environment in which dietary intake of saturated fat is accurately determined by a professional).
In 4 RCTs in which individuals started with diets high in saturated fat and reduced saturated fat intake by 10% of energy intake, a 12-15% decrease in total cholesterol was seen, and this was associated with a significant reduction in cardiovascular disease (Circulation. 1969. 60. 111S-163S; Circulation. 1970. 42. 935-942; Int J Epidemiol. 1979. 8. 99-118 as cited in the Comment section of JAMA. 2006. 295. 655-666).
A diet low in simple sugars and low in high glycemic index carbohydrates may raise HDL. In one study in 14 young men, increased intake of sucrose from 115 to 260 grams/day was associated with 16% decrease in HDL (Br Med J. 1980. 281. 1396).
Addition of soluble fiber – a meta-analysis of 67 controlled trials of dietary soluble fiber as a single intervention shows only a modest effect on TC and LDL (i.e. decrease of 5 mg/dL) [Am J Clin Nutr. 1999. 69. 30-42].
More information below under the heading of herbs – see konjac root and psyllium.
There is some data that rye fiber lowers cholesterol and blood sugar more than wheat fiber (Am J Clin Nutr. 2003. 77. 385-391).
A plant-based diet
in a 4 week outpatient feeding study in 120 adults, the group that incorporated more vegetables, legumes, and whole grains into a low fat diet (AHA Step I guidelines) achieved an average 17.6 mg/dl drop of total cholesterol compared to an average 9.2 mg/dl drop in the low fat control group (P=0.01) and an average 13.8 mg/dl drop in LDL compared to an average7.0 mg/dl drop in the low fat control group (P=0.02). The HDL dropped an average of 3.8 mg/dl in the plant group compared to an average of 2.5 mg/dl in the control group (P=0.13) and the triglycerides increased an average of 0.1 mg/dl in the plant group compared to 1.2 mg/dl in the control group (P>0.2). The two diets in this study were designed to have identical levels of total fat (30%), saturated fat (10%), and cholesterol (<300 mg/day) [Ann Intern Med. 2005. 142. 725-733].
A review of 27 clinical trials, a mix of RCTs and observational trials found that a plant based diet lowered LDL cholesterol as much as 35% (Am J Cardiol. 2009. 104. 947-956 and editorial 957-958)
to alirocumab) demonstrate good safety (Am J Cardiol. 2016. 118. 1805-1811).
In a network meta-analysis of 17 RCTs (n = 13,083), PCSK9 inhibitors reduced LDL cholesterol by 57% compared with placebo, by 36% compared with ezetimibe (Zetia), and reduced all-cause mortality by 57% from 0.5% to 0.2%, but did not significantly reduce cardiovascular events or major adverse CV events. Neurocognitive adverse events were increased by 133% from 0.3% to 0.7% (Eur Heart J. 2016. 37. 536-545)
A meta-analysis of 24 RCTs (n = 10,159) show that PCSK9 inhibitors are associated with a 47% reduction in LDL cholesterol, and 26% reduction in Lipoprotein (a), compared with placebo or ezetimibe (Zetia) control groups (Ann Intern Med. 2015. 163. 40-51 and editorial 64-65).
Reduction in LDL cholesterol was similar in patients on statins and those not on statins; reductions in LDL were greater in the placebo group than in those on ezetimibe.
Most patients involved patients treated with statins who did not meet LDL goals; some trials focused on patients with intolerance to statins.
Fully humanized monoclonal antibodies have been developed (evolocumab, alirocumab, and bococizumab) which disrupt the interaction between PCSK9 and the LDL receptor – by inactivating PCSK9, these drugs decrease LDL receptor degradation, and increase recirculation of the receptor to the surface of the hepatocyte, thus lowering LDL levels in the bloodstream.
In the FOURIER trial, a 48 week RCT of evolocumab either 140 mg sub q every 2 weeks or 420 mg sub q monthly, in 27,564 patients with atherosclerotic cardiovascular disease, on statins,and with a median LDL cholesterol of 92 mg/dl, LDL levels were lowered to 30 mg/dl in the treatment group and there were reduced cardiovascular events in the treatment group at a median follow up of 2.2 years (N Engl J Med. 2017. 376. 1713-1722 and editorial 1790-1791).
In the ODYSSEY OUTCOMES trial, a RCT of 18,924 patients with acute coronary syndrome within 1 -12 months prior to trial and taking high-intensity statin treatment at trial entry, those randomized to receive alirocumab 75 mg sub q every 2 weeks had a lower composite primary endpoint of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization (9.5% vs. 11.1%, HR 0.85) at a median follow up of 2.8 years. The investigators calculated that 49 patients would need to be treated for 4 years to prevent the occurrence of one of the primary endpoints. Goal LDL in this trial was 25 -50 mg/dl; 750 patients were switched from treatment to placebo because they had two consecutive measurements of LDL cholesterol < 15 mg/dl on a reduced dose (75 mg) of alirocumab. Note that there was not a significant reduction in the secondary endpoints of death from coronary heart disease or death from cardiovascular causes (N Engl J Med. 2018. 379. 2097-2107 and editorial 2161-2162),
LDL - not all is created equal:
Pattern A - large particles.
Pattern B - small, dense particles.
At any given LDL value, people with pattern B are three times more prone to heart disease than those with pattern A.
Hormone replacement therapy in women seems to have a much greater impact on LDL and HDL cholesterol values in those with pattern B.
Doctors can order the test which measures LDL particle size from Berkeley Heart Lab at 1-800-HEART-89.
Oxidized LDL is the real culprit
There is data that the ratio of oxidized LDL to HDL is a more potent biomarker for discriminating between subjects with and without CAD than the lipid profile (Am J Cardiol. 2006. 97. 640-645).
Sources of oxidized cholesterol include food preparation (i.e. scrambling eggs rather than preparing sunny side up or hard-boiling) and oxidation of cholesterol in the body.
Co Q 10 protects against oxidation of cholesterol.
Phenols in virgin olive oil protect against oxidation of cholesterol J Nutr. 2010. 140. 501-508).
Causes/biomarkers of oxidation of cholesterol (Pizzorno J. Editorial – Table 1. IMCJ. 2014. 13. 8-14).
Cooking foods with high cholesterol content at high temperatures
Inadequate blood glutathione levels
Toxic metal body burden
Deficiency of antioxidant nutrients
Eating rancid oils
HDL – not all is created equal (Cleve Clin J Med. 2007. 74. 697-705)
In most healthy people, HDL has an anti-inflammatory role, facilitates reverse cholesterol transport, and limits the production of oxidized LDL.
In the setting of systemic inflammation, HDL can become dysfunctional, and actually have pro-inflammatory effects.
A monocytes chemotaxis assay and a cell free assay, not yet commercially available in 2007, can determine the functional characteristics of HDL.
Dysfunctional HDL is may be present in the post-operative period after surgery, in individuals consuming a diet high in saturated fat, and in individuals with acute infections such as influenza or sepsis, autoimmune diseases, coronary artery disease, and diabetes.
Statins can modify HDL’s properties from pro-inflammatory to anti-inflammatory, based on small clinical trials (Circulation. 2003. 108. 2751-2756; presentation ACC in 2007).
BEWARE that pharmacological agents which raise HDL may nonetheless have an adverse effect on its functional characteristics. This may explain why torcetrapib, a cholesteryl ester transfer protein inhibitor which raised HDL 100% in early clinical trials was nonetheless associated with a 61% higher all cause mortality in a subsequent clinical trial, and was thus not brought to market (Arterioscler Thromb Vasc Biol. 2007. 27. 257-260).
Triglycerides and heart disease - see ‘Additional Risk factors for coronary heart disease at the bottom of this outline
Cost effectiveness of cholesterol lowering with medications (based on modeling): Note, with availability of generic statins, cost effectiveness is currently much greater.
Primary prevention in males and females with cholesterol greater than 300 (Ann Intern Med. 2000. 132. 769-779)
Age 25-34: $1,000,000 - $10,000,000/year of life saved.
Age 55-64: $100,000/year of life saved.
Note cardiac transplant only costs an estimate $50,000/year of life saved.
Secondary prevention (Ann Intern Med. 2000. 132. 769-779)
In middle aged adults with established coronary artery disease, carotid artery disease, or peripheral vascular disease statins may actually be cost saving, and costs at most $10,000/QALY.
In patients over age 75 with a history of myocardial infarction, statins cost anywhere from $5400/QALY to $97,800/QALY, depending on the modeling assumptions
History (Viewpoint. JAMA. 2014. 311. 461-462)
Cholesterol identified as a treatable risk factor for heart disease based on data from the Lipid Research Clinics Program trial which showed that cholestyramine treatment of high cholesterol in men was associated with a reduction in risk of CHD (JAMA. 1984. 251. 351-364).
Data from epidemiological studies, animal studies, and family studies all supported cholesterol as a treatable risk factor.
NCEP/ATP I (Arch Intern Med. 1988. 148. 36-69)
LDL level of 160 selected as abnormal in part because it was the value above which the risk of CHD increased more rapidly and in part because at the time it represented approximately the 75th percentile for the US population.
These recommendations thus declared one quarter of the adult population as having a treatable risk factor for CHD (at a time when few safe and effective therapies were available).
This report specified whether or not each recommended drug treatment had been shown to reduce clinical events.
NCEP/ATP II (JAMA. 1993. 269. 3015-3023)
Increased emphasis on total heart disease risk as a guide to treatment.
The goal for secondary prevention is LDL < 100, with a recommendation to start medication if LDL > 130 after a trial of lifestyle changes.
Age > 45 in males and age > 55 in females is added as a risk factor for heart disease.
Recommendation to use an LDL cutoff of 220 instead of 190 with regard to the threshold for starting medication treatment in low risk males under age 35 and low risk females under age 45.
Increased emphasis on HDL cholesterol as a heart disease risk factor.
Recommend include HDL measurement any time a screening cholesterol is ordered.
Designation of HDL > 60 as a negative risk factor for heart disease.
Designation of HDL < 35 as an additional positive risk factor for heart disease.
Increased emphasis on exercise and weight loss (in addition to diet).
Decision tree diagrams.
NCEP/ATP III (JAMA. 2001. 285. 2486-2497) and update (Circulation. 2004. 110. 227-239).
Focus on multiple risk factors.
Persons with diabetes are considered a CHD risk equivalent.
Uses Framingham projections of 10 year absolute CHD risk.
Identifies persons with multiple metabolic risk factors as candidates for intensified therapeutic lifestyle changes.
Modifications of lipid and lipoprotein classification.
Identifies LDL cholesterol < 100 mg/dl as optimal.
Raises categorical low HDL cholesterol from <35 mg/dl to < 40 mg/dl.
Lowers the triglyceride classification cutpoints, such that triglycerides >200 mg/dl are high.
Support for implementation.
Recommends complete lipoprotein profile instead of just cholesterol and HDL cholesterol for screening.
Encourages use of plant sterols/stanols and soluble fiber as therapeutic dietary options to lower LDL cholesterol.
Presents strategies for promoting adherence to therapeutic lifestyle changes and drug therapies.
Recommends treatment beyond LDL lowering in individuals with triglycerides > 200 mg/dl.
Identified statins as the ‘usual drug’ for starting therapy, but did not in the report clearly identify which of the recommended drugs had been shown to reduce clinical events.
ACC/AHA (American Heart Association and American College of Cardiology) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” (Stone NJ et al. Circulation. Epub 11/12/2013; Stone NJ et al. Ann Intern Med. 2014. 160. 339-343).
The aspect of this guideline receiving the most publicity is the recommendation for moderate or high intensity statin therapy for the primary prevention of atherosclerotic cardiovascular disease in individuals with 7.5% or greater 10 year atherosclerotic cardiovascular disease risk, and consideration of moderate-intensity statin treatment for individuals with a 5% to 7.5% 10 year risk. Risk calculator at http://tools.cardiosource.org/ascvd-risk-estimator/
Exceptions are adults with New York Heart Association heart failure class II – IV and those receiving maintenance hemodialysis, as statins have not been shown to reduce risk in trials performed in these populations.
NOTE that 32.9 % of individuals aged 40-75 fall into the risk category for which prescription statin treatment is recommended.
Guideline emphasizes shared decision making, and emphasizes adherence to ha healthy diet.
As with NCEP/ATP III, this guideline creates 4 categories of adults, with distinct recommendations for each group:
Adults with atherosclerotic cardiovascular disease (includes ACS, MI, stable angina, coronary or other arterial revascularization, stroke, TIA, PVD of atherosclerotic origin – initiate high intensity statin treatment.
Adults with LDL cholesterol levels of 190 mg/dl or higher – initiate high intensity statin treatment.
Adults with diabetes, aged 40-75 with LDL between 70 and 189 mg/dl – initiate moderate or high intensity statin treatment.
Adults age 40-75 with LDL between 70 and 189 mg/dl and a 7.5% or greater 10 year risk of atherosclerotic cardiovascular disease – initiate moderate or high intensity statin treatment.
High, moderate, and low intensity statin treatment
High (>50% lowering of LDL cholesterol): atorvastatin 40-80 mg daily, rosuvastatin 20 mg daily
Moderate (30-50% lowering of LDL cholesterol): atorvastatin 10 mg daily, rosuvastatin 10 mg daily, simvastatin 20-40 mg daily, pravastatin 40 mg daily, lovastatin 40 mg daily, fluvastatin 40 mg twice a day
Low (20-30% lowering of LDL cholesterol): pravastatin 10-20 mg daily, lovastatin 20 mg daily
What’s New in these guidelines
The task force found no scientific evidence to support specific treatment goals for LDL or HDL cholesterol. Thus the LDL and HDL treatment targets which characterized the first 3 reports have been abandoned.
Routine monitoring of ALT, AST, and CPK is not recommended – measurement is recommended only in those with symptoms.
In contrast with NCEP/ATP III, this guideline focuses on major disease endpoints (rather than surrogate markers) in regard to assessment of efficacy of different classes of medications, and concludes based on the evidence that statins should be first line (rather than fibrates, niacin, bile acid sequestrants, ezetimibe, or omega 3 fatty acids).
The core of the guidelines depends on a new risk score, referred to as the “Pooled Cohort Equations,” using data from 5-NHLBI-sponsored longitudinal, population based cohorts African Americans and non-Hispanic white men and women. There is some data that this score may overestimate risk, but there is much uncertainty regarding the extent of any overprediction (Viewpoint. Ioannidis JPA. JAMA. 2014. 311. 463-464). Risk calculator at http://tools.cardiosource.org/ascvd-risk-estimator/
History and process of creation of this guideline
Work on these guidelines began in 2008, and the panel adhered to the standards of the IOM study committee, which published in 2011 “Clinical Practice Guidelines We Can Trust.”
This process involves focusing on select clinical questions (3 questions relevant to clinical care and 5 additional critical questions) which are to be answered in the guideline based entirely upon RCT evidence.
The panel included cardiologists, epidemiologists, primary care physicians, and epidemiologists.
Several meta-analyses of up to 27 RCTs were available as evidence.
Draft recommendations were reviewed by 23 experts and representatives of federal agencies identified by the NHLBI.
In 2013, the NHLBI announced its plan to turn over guideline development to the ACC/AHA.
Critique – 8 of the 15 panelists had current or recent industry ties (BMJ. 2013. 347. f6989).
United States Preventive Services Task Force (USPSTF) [JAMA. 2016. 316. 1997-2007].
Recommend initiating low to moderate dose statins for adults ages 40 - 75 who do not have a history of CVD but who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), and a calculated 10-year CVD event risk of 10% or greater (Grade B).
Selectively offer low to moderate dose statins for adults ages 40 - 75 who do not have a history of CVD but who have one or more CVD risk factors, and a calculated 10-year CVD event risk of 7.5% - 10% (Grade C).
Current evidence is insufficient to make a recommendation regarding statins and primary prevention in those over age 75 (Grade ().
Additional risk factors and risk markers for coronary heart disease
Systematic reviews done for the USPSTF concluded that “The current evidence does not support the routine use of any of the 9 risk factors for further risk stratification of intermediate-risk persons.” The 9 risk factors studied are CRP level, CAC score, lipoprotein (a) level, homocysteine level, leukocyte count, fasting glucose concentration, periodontal disease, ankle-brachial index, and carotid IMT (Ann Intern Med. 2009. 151. 496-507).
This is a highly sensitive measure of inflammation.
Optimal ratio is less than 3.
ADMA (asymmetric dimethyl arginine)
Naturally occurring compound that inhibits nitric oxide production and impairs endothelial function, and is an important risk factor for coronary artery disease.
Initially described in 1992 by Patrick Vallance, an endothelial cell biologist.
This is an analog of L-arginine that binds to endothelial nitric oxide synthase (eNOS) and by binding inhibits the conversion of L-arginine to nitric oxide.
This compound can be measured in the plasma. The most meaningful lab value is probably the ratio of L-arginine to ADMA, with 50:1 – 100:1 considered a healthy ratio.
If ratio is suboptimal, treatment consists of supplemental L-arginine.
Apolipoprotein B: Apolipoprotein A-1 ratio
This is a strong risk factor for atherosclerotic cardiovascular disease.
Several publications endorsed this ratio as an improved measure of risk (Lancet. 2001. 358. 2026-2033; Lancet. 2004. 364. 937-952; J Intern Med. 2006. 259. 247-258).
In a prospective, nested case-control study in which 869 cases of fatal or nonfatal CAD were compared with 1511 controls, in the European Prospective Investigation into Cancer and Nutrition Norfolk Study, this ratio added little to existing measures of CAD risk (Ann Intern Med. 2007. 146. 640-648 and editorial 677-679).
In a prospective cohort of 3322 middle-aged white participants in the Framingham Study, after a median follow up of 15 years, this ratio did NOT offer any incremental utility over the chol: HDL ratio (JAMA. 2007. 298. 776-785).
Measure of iron stores, and high levels are associated with increased oxidative stress.
Optimal level is <150 for females and <300 for males.
If levels are high, sweating and the supplement inositol hexaphosphate (IP6) facilitate excretion of excess iron
Involved in the formation of a blood clot; high levels increase the risk for formation of blood clots.
Optimal levels are 150-299 mg/dl, with levels above 460 mg/dl indicating a high risk.
High level might be partially caused by vitamin C insufficiency (BMJ. 1995. 310. 1559-1563).
Nattokinase is a plant-derived dietary supplement that can lower fibrinogen levels (J Agric Food Chem. 2000. 48. 3210-3216).
Vitamin C – recommended by Thomas E Levy (Stop America’s #1 Killer! 2006. Pg 112).
GGT (gamma glutamyltransferase)
This enzyme which is mainly produced in the liver and catalyzes the antioxidant glutathione is an independent predictor of CVD death, based on data from 164,000 Australian adults followed for up to 17 years (Circulation. 2005. 112. 2130-2137).
Hypothetical mechanism – depletion of glutathione. Thus, hypothetically, supplemental NAC might offset the increased risk associated with high GGT levels.
Amino acid derived from methionine which is an independent risk factor for coronary artery disease.
A meta-analysis shows that the hazard ratio for a recurrent event increases by 16% for each increase of 5 micromol/liter in serum homocysteine concentration (BMJ. 2002. 325. 1202).
Kilmer McCully first proposed in 1969 that homocysteine causes atherosclerosis.
Physiological roles are to regulate bone and tissue formation and to stimulate formation of IGF-1.
Homocysteine levels are also correlated with risk of CVA, DVT, and a variety of neurological diseases. Observational data suggest that homocysteine is neurotoxic.
Ideal homocysteine level is probably less than 6 micromol/liter, even though most labs define normal as less than 9 micromol/liter.
Factors which raise homocysteine levels
Chronic high consumption of alcohol
Chronic renal failure
Diet high in saturated fat (Dr.Perlmutter)
Carbemazepine (Tegretol) and phenytoin (Dilantin) lower folate concentrations
Primidone (Mysoline) and valproate (Depakote) deplete B vitamins too (Dr Perlmutter)
Aspirin (Dr Perlmutter)
Bezafibrate in combination with niacin via an uncertain mechanism
Cholestyramine (Questran) and colestipol (Colestid) impair folate absorption
Colestipol in combination with niacin via an uncertain mechanism
COX2 inhibitors (i.e. Celebrex) - (Dr Perlmutter)
Estrogens (i.e. oral contraceptives, ERT) deplete vitamin B6
Fenofibrate in combination with niacin via an uncertain mechanism
H2 blockers (Dr Perlmutter)
Hydralazine (Dr Perlmutter)
Hydrochlorothiazide raises homocysteine level by 16% on average (Metabolism. 2003. 52. 261)
Levodopa (Dr Perlmutter)
Loop diuretics (Dr Perlmutter)
Methotrexate lowers folate levels by depleting folate metabolites
NSAIDS (Dr Perlmutter)
Raloxifine / Evista - (Dr Perlmutter)
Steroids, including inhaled and nasal steroids (Dr Perlmutter)
Theophylline lowers vitamin B6 levels
Trimethoprim (Dr Perlmutter)
Insufficiency of vitamin B6, B12, or folate - vitamin B12 is a more important determinant of elevated homocysteine concentrations in older people than is folate (Age Ageing. 2004. 33. 34-41).
Lead (as per Sherry Rogers, MD)
Menopause (Metabolism. 1985. 34. 1073-77).
Ways to mitigate the effect of high homocysteine (i.e. increasing coagulability or stickiness of the blood) – vitamins C and .
Ways to lower homocysteine levels:
Diet – limit coffee consumption, and increase soy consumption. Soy protein with native phytate significantly reduces homocysteine (Am J Clin Nutr. 2006. 84. 774-780).
Vitamin B9 (folate) 0.5 – 5 mg/day or 5-MTHF.
Vitamin B12 100 - 1000 mcg/day.
Vitamin B6 10 – 100 mg/day.
Vitamin B2 (riboflavin) 100 mg/day (may be beneficial for those with MTHFR 677TT genotype)
Zinc 30 mg/day.
If refractory hyperhomocysteinemia (especially postprandial hyperhomocysteinemia) consider betaine 1.5 – 6 grams/day, either anhydrous betaine (TMG) or betaine hydrochloride.
If hyperhomocysteinemia secondary to hemodialysis, consider NAC 1200 mg twice a day.
Homocysteine levels are correlated with an increased risk of heart disease.
A meta-analysis of observational studies showed that a 5 umol/L higher homocysteine level was associated with a 70% increase in the risk of heart disease (JAMA. 1995. 274. 1049-1057).
A meta-analysis of both prospective and retrospective studies showed weaker associations of high homocysteine values in prospective studies, such that a 5 umol/L higher homocysteine level was associated with a 30% increase in the risk of heart disease (J Cardiovasc Risk. 1998. 5. 229-232).
The data regarding the benefits of lowering homocysteine is mixed, with observational trials showing benefit and most RCTs showing no benefit. The data in aggregate would suggest that homocysteine is a biomarker for cardiovascular risk, rather than a modifiable risk factor.
Restenosis post stent placement – one review of published data showed that folate reduced the risk of restenosis after angioplasty from 37.6% to 19.6% (Ann Med. 2003. 35. 156-163), but in a separate study, patients with stents treated with folate, vitamin B12, and vitamin B6 had an increased rate of in-stent restenosis (N Engl J Med. 2004. 350. 2673-2681).
In a cohort study of 80,082 nurses in the Nurses’ Health Study followed for 14 years, those women taking a multivitamin and those women with higher dietary folate intake had a lower risk of fatal and nonfatal MI (JAMA. 1998. 279. 359-364).
A meta-analysis of prospective observational studies showed that a 25% reduction in homocysteine (approximately 3 umol/L) is associated with an 11% lower risk of heart disease and a 19% lower risk of stroke (JAMA. 2002. 288. 2015-2022).
A meta-analysis of case-control studies examining risk of heart disease and stroke as a function of genetic variants in the 5-MTHFR enzyme show that a 3 umol/L difference in homocysteine levels among individuals with the TT genotype as compared with the CC genotype is associated with a 10-15% difference in CHD risk and a 20-25% difference in CVA risk (Lancet. 2005. 365. 224-232).
The concordance of the results in prospective and genetic studies provides support for a causal relationship between elevated plasma homocysteine levels and vascular disease risk (BMJ. 2006. 333. 1114-1117).
In the CHAOS-2 trial, supplementation with folate, vitamin B12, and vitamin B6 was not associated with a reduction in cardiovascular risk (Circulation. 2002. 106. Suppl II).
In the VISP trial in which 3680 patients with stroke were randomized to different daily doses of folate, vitamin B12, and vitamin B6, after two years there was a dose dependent reduction in homocysteine concentration, but no significant difference in the rates of vascular events (JAMA. 2004. 291. 565-575).
In the NORVIT trial in 3749 subjects who had had a MI within 7 days before randomization into one of four groups (placebo, folate 0.8 mg + vitamin B12 0.4 mg + vitamin B6 40 mg, folate 0.8 mg + vitamin B12 0.4 mg, or vitamin B6 40 mg), at a mean of 40 months of follow-up, and with 90% compliance, even though the homocysteine level dropped within 2 months an average of 27% in the folate + vitamin B12 group compared to placebo, the incidence of cardiovascular events in all active treatment groups (composite endpoint of recurrent MI, stroke, or sudden death attributed to CAD) was not different from placebo. There was actually a trend toward an increased risk in the composite endpoint in the treatment group administered folic acid, vitamin B6, and vitamin B12 (p=0.050 [N Engl J Med. 2006. 354. 1578-1588].
In the HOPE 2 trial in 5222 patients over age 55 with vascular disease or diabetes, those who received 2.5 mg folate daily with 50 mg vitamin B6 daily and 1 mg vitamin B12 daily had a mean decrease in homocysteine of 2.4 micromol/liter, but there was no difference in death from cardiovascular causes, MI, or any of the secondary endpoints. Risk of stroke in the active treatment group was significantly lower (RR=0.75, 0.59-0.97) but the risk of hospitalization for unstable angina was increased in the active treatment group (1.24, 1.04-1.49) [N Engl J Med. 2006. 354. 1567-1577].
In a meta-analysis of 12 RCTs, including the above 4 studies and 8 smaller studies, the relative risk for heart disease was 1.04 and the relative risk for stroke was 0.86 (JAMA. 2006. 296. 2720-2726).
In the HOST trial in 2056 patients with advanced chronic kidney disease(GFR<30), those who received a daily vitamin capsule containing 40 mg of folate, 100 mg of vitamin B6, and 2 mg of vitamin B12, showed a reduction in homocysteine from a mean of 24 umol/L to 18 umol/L, but there was no significant effect on mortality or any significant effect on any of the secondary outcome measures, including MI, CVA, amputation, time to dialysis, or time to thrombosis in hemodialysis patients (JAMA. 2007. 298. 1163-1170).
In the WAFACS study in 5442 high risk women (health professionals) followed for a mean of 7.3 years, a combination pill of 2.5 mg of folate, 50 mg of vitamin B6, and 1 mg of vitamin B12 did not reduce the combined endpoint of total cardiovascular events (JAMA. 2008. 299. 2027 and editorial 2086-2087).
In WENBIT, a secondary prevention trial in western Norway using a 2 x 2 factorial design in 3096 patients with coronary artery disease (most patients had stable coronary artery disease), even though mean total homocysteine was lowered 30% after one year, at a median of 38 months of follow up, there was no effect of treatment on total mortality of cardiovascular events. Treatment groups included (1) folate 0.8 mg/day + vitamin B12 0.4 mg/day + vitamin B6 40 mg/day, (2) folate + vitamin B12, (3) vitamin B6 alone, and (4) placebo. Primary endpoint was a composite of all-cause death, nonfatal acute MI, acute hospitalization for unstable angina, and nonfatal thromboembolic stroke (JAMA. 2008. 300. 795-804).
In a cohort study of 492 patients with early onset CAD followed for a median of 115 months, folate based vitamin therapy (>400 mcg/day supplemental folate) was associated with lower all cause mortality in those with elevated homocysteine levels at baseline, but not in those with normal homocysteine levels at baseline (Am J Cardiol. 2009. 104. 745-749).
In the WAFCAS cardiovascular prevention study, a RCT in ~4200 middle aged female health professionals at risk for cardiovascular disease and type 2 diabetes, a combination pill of 2.5 mg folate, 50 mg B6 and 1 mg B12 was ineffective at reducing the risk of developing diabetes and ineffective at reducing the risk of developing heart disease. Median follow up was 7.3 years, and lack of clinical benefit was in spite of the fact that supplementation did lower homocysteine levels 18.5% (Diabetes. 2009. 58. 1921-1958).
In the SEARCH trial, a RCT in 12,064 survivors of MI in secondary care hospitals in the UK between 1998 and 2008, 2 mg folate + 1 mg B12 daily was associated at average follow up of 6.7 years with substantial reductions in blood homocysteine levels, but no beneficial effect on vascular outcomes. There were no associated adverse effects of long term supplementation or adverse effects of supplementation on cancer outcomes (JAMA. 2010. 303. 2486-2494).
In the VITATOPS study, a secondary prevention RCT of 8164 patients who experienced a stroke or TIA within the previous 7 months, those who received the combination of folate 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg daily showed a 9% relative risk reduction and a 1.56% absolute risk reduction in the primary endpoint, a composite of stroke, MI, or vascular death, at a median follow up of 3.4 years (p=0.05). The NNT for 3.4 years to prevent one stroke or MI or vascular death was 64 (Lancet Neurol. 2010. 9. 855-865).
A meta-analysis of 8 RCTs of folic acid supplementation, involving 37,485 individuals, showed that despite an average 25% reduction in homocysteine level, during a median follow up of 5 years, there was no significant effect on major vascular outcomes, major coronary events, overall vascular mortality, overall cancer mortality, or all-cause mortality (Arch Intern Med. 2010. 170. 1622-1630).
Mechanisms by which folate might offset the homocysteine-lowering benefit, and thus lead to the failure to improve outcomes seen in the above trials include:
Folate may promote cell proliferation in atherosclerotic plaque (N Engl J Med. 2006. 354. 1629-1632. Editorial).
Folate may alter the methylation potential in vascular cells, promoting the development of plaque (N Engl J Med. 2006. 354. 1629-1632. Editorial).
Folate may promote methylation of arginine to ADMA (asymmetric dimethylarginine), a substance which inhibits the activity of nitric oxide synthase (N Engl J Med. 2006. 354. 1629-1632. Editorial).
Folate in most supplements (and fortified foods) is pteroylmonoglutamate (PGA), a form that does not occur in nature, may be relevant. At doses below 0.4 mg daily, all PGA is converted into biologically active methylfolate during absorption. At higher doses, there is synthetic PGA in the blood and the long term ramifications of this are unknown (BMJ. 2004. 328. 211-214).
Folate supplementation may predispose to zinc deficiency, and zinc deficiency might increase the risk of CHD.
Possible explanations for the failure of randomized controlled trials to demonstrate reductions in cardiovascular mortality in association with homocysteine lowering include (critique offered by Alan Gaby, MD):
Vitamin B6 supplementation may deplete magnesium, and magnesium supplementation was not administered in these trials.
Folate supplementation may deplete zinc, and zinc supplementation was not administered in these trials.
Magnesium and zinc status are marginal in Western societies. Furthermore, magnesium and zinc deficiencies may be exacerbated in high-risk patients by consumption of atherogenic diets and by the use of zinc-depleting cardiac medications (i.e. diuretics, digoxin, ACE inhibitors).
Even if homocysteine lowering does not reduce cardiovascular mortality, there is evidence that homocysteine lowering reduces the risk of osteoporotic fractures and may decrease the risk of Alzheimer’s disease.
hs-CRP (high sensitivity C reactive protein)
This is a protein synthesized by the liver and it is a marker for inflammation, and an independent risk marker for coronary artery disease (CAD), although the magnitude of the association has been downgraded (N Engl J Med. 2004. 350. 1387-1397).
In 2006 it remains unclear whether CRP is causally related to the cardiovascular disease, or just a risk marker.
There is ongoing study and debate with regard to the extent to which measurement of hs-CRP alters cardiovascular risk assessment (Editorial. Ann Intern Med. 2006. 145. 70-72).
Data at 10 years of follow-up in the Women’s Health Study (an observational cohort study) shows that global risk assessment model that includes hs-CRP improves risk classification in women, particularly amongst those with a 10 year risk of 5-20% (Ann Intern Med. 2006. 145. 21-29).
A narrative review of the literature published prior to 1/06 concludes that there is no definitive evidence that adding CRP to models adds substantial predictive value (Ann Intern Med. 2006. 145. 35-42).
In an 8 year prospective observational cohort study in 1949 men and 2497 women from the Framingham Heart Study who did not have CAD as baseline, elevated CRP level provided no further prognostic information beyond traditional risk factor assessment (Arch Intern Med. 2005. 165. 2473-2478).
CRP can fluctuate as much as 44% over the course of a woman’s menstrual cycle.
Factors which raise hs-CRP.
High AGE (advanced glycation end products) content of the diet – in a study in which diabetics consumed 2 similar diets that differed 5-fold in their AGE content, achieved by varying the cooking time and temperature, serum AGEs increased by 65% on the high-AGE diet, and C-reactive protein increased by 35% on the high-AGE diet (Proc Natl Acad Sci. 2002;99:15596-15601).
High saturated fat intake raises hs-CRP.
High trans-fat intake raises hs-CRP (J Nutr. 2005. 135. 562-566).
High glycemic-index foods raise hs-CRP by promoting excess production of IL-6 (Am J Nutr. 2002. 75. 492-498). Cross-sectional data in 15,033 women in the Women’s Health Study also show this association.
Low magnesium intake – those adults who consumed less than the RDA were 1.48-1.75 times more likely to have an elevated CRP (J Am Coll Nutr. 2005. 24. 166-171).
Oral estradiol and Premarin raise hs-CRP (topical estradiol does not).
Factors which lower hs-CRP
Alpha tocopherol and gamma tocopherol
Alcohol in moderation lowers hs-CRP, independent of the type of alcoholic beverage consumed, based on data in 11,815 participants in the Women’s Health Study (Am J Cardiol. 2005. 96. 83-88).
Co Q 10 (in a study in baboons, in conjunction with vitamin E).
Curcumin - conjugation with cyclodextrin increases absorption, increasing peak plasma concentration
High antioxidant diet - statistically significant decrease in hs-CRP of questionable clinical significance (3.0 mg/L to 2.5 mg/L) shown in a small clinical trial (Am J Clin Nutr. 2008. 87. 1290-1294).
Low AGE (advanced glycation end products) content of the diet – in a study in which diabetics consumed 2 similar diets that differed 5-fold in their AGE content, achieved by varying the cooking time and temperature, serum AGEs decreased by 30% on the low-AGE diet, and C-reactive protein decreased by 20% on the high-AGE diet (Proc NatlAcad Sci. 2002. 99. 15596-15601).
Exercise (Epidemiology. 2002. 13. 561-568).
Fiber lowers hs-CRP
Epidemiologic data comes from NHANES (J Nutr. 2004. 134. 1181-1185).
Cross-sectional data in 15,033 women in the Women’s Health Study also show this association, and further link the association to intake of soluble fiber.
In a yearlong study in 524 healthy adults, those who ate the most fiber had lower hs-CRP levels (Am J Clin Nutr. 4/06).
A randomized crossover intervention trial in 28 women and 7 men showed that fiber intake of 30 gm/day, both from a diet naturally rich in fiber and also from a fiber supplement reduces CRP (Arch Intern Med. 2007. 167. 505-506).
Data on a total of 11,113 subjects in NHANES 2005-2010 suggest that “A greater amount of dietary fiber intake might be associated with lower C-reactive protein levels” (Am J Cardiol. 2014. 113. 287-291).
Fish oil (J Nutr Biochem. 2003.14. 513-521).
Grape seed extract 300 mg/day
L-carnitine lowers hs-CRP.
Magnesium might lower hs-CRP (in those who are deficient) based on data that low magnesium intake is associated with high CRP (J Am Coll Nutr. 2005. 24. 166-171).
Mediterranean diet lowers hs-CRP (JAMA. 2004. 292. 1440-1446).
Multivitamin lowers hs-CRP as much as 32%, based on published data from the Cooper Institute and using “Cooper Complete” (Am J Med. 2003. 115. 702-707).
Resveratrol – conjugation with cyclodextrin increases absorption, increasing peak plasma concentration
Vitamin C – in a RCT of 369 healthy nonsmokers, analysis of the subgroup with CRP > 1 mg/L at baseline showed that vitamin C 1 gram daily lowered the median level by 25% (p=0.02). In a second arm of this trial, vitamin E 800 IU per day had not effect (Free Radic Biol Med. 2009. 46. 70-77).
Vitamin D3 (QJM. 2002. 95. 787-796).
Weight loss lowers hs-CRP, based on a systematic review of 33 studies. For each 1 kg of weight loss, the mean change in CRP level was -0.13 mg/L (Arch Intern Med. 2007. 167. 31-39).
Zinc – in a 6 month RCT in 44 seniors, mean age of 66, those taking 45 mg per day of zinc, as zinc gluconate, experienced a drop of CRP from 2.46 mcg/l to 1.90 mcg/l (p=0.015) whereas the placebo patients experienced a nonsignificant increase in CRP level (Am J Clin Nutr. 2010. 91. 1634-1641).
Lipoprotein (a) Cleveland Clinic Journal of Medicine. 1999. 66. 465-466.
Consists of an LDL molecule bound by a disulfide linkage to a glycoprotein, lipoprotein (a).
Independent risk factor for coronary artery disease, risk marker for aortic sclerosis.
Lp (a) is atherogenic.
Lp (a) is structurally similar to plasminogen, and thus might inhibit fibrinolysis.
Levels are largely genetically determined.
Vitamin C deficiency might trigger a rise in Lp (a) as a compensatory mechanism – hypothesis of Thomas Levy, MD (Townsend Letter. May 2011. 46-57)
Lp (a) plasma levels increase as vitamin C levels decline (Proc Natl Acad Sci U S A. 1990. 87. 6204-6207).
Lp (a) can accelerate wound healing and assist in cellular repair (Nature. 1987. 330. 113-114).
Trans fat consumption raises Lp (a).
Using 30 mg/dl as the upper limit of normal, it is estimated that 25% of the U.S. population has high levels.
Lifestyle modifications such as diet, weight loss, and exercise have no effect on levels.
Vitamin C supplementation may protect against Lp (a) induced damage. Fish oil, L-carnitine, L-lysine, and L-proline may also neutralize Lp (a).
Estrogen replacement therapy, high dose niacin, and fenofibrate lower Lp (a) but resins (Questran, Colestipol) and statins (Lipitor, Mevacor, etc.) do not.
Coenzyme Q 10 - a meta-analysis of 7 RCTs (n = 409) showed that doses of 100 - 300 mg/day for 4-12 weeks associated with slight but statistically significant decrease in mean Lp (a) levels of 3.54 mg/dl (Pharmacol Res. 2016. 105. 198-209).
L-carnitine 1 gram twice a day
Lowers Lp (a) 8-12%, based on a RCT of 36 patients (Nutr Metabol Cardiovasc Dis. 2000. 10. 247-251).
In combination with simvastatin 20 mg/day, lowers Lp (a) statistically more than simvastatin alone (p < 0.02) in a 12 week trial of 58 patients with mixed hyperlipidemia (Lipids. 2017. 52. 1-9).
Lysine – Linus Pauling hypothesized that this would decrease Lp (a) binding to the arterial wall and might even dislodge Lp (a) bound to the wall (Thomas E Levy Stop America’s #1 Killer! 2006. Pg 114).
Niacin 2-3 gm/day can reduce levels by 20-50% after 8 weeks (J Intern Med. 1989. 226. 271-276).
Resveratrol may lower Lp (a).
Vitamin C – recommended by Thomas E Levy (Stop America’s #1 Killer! 2006. Pg 112).
Consider measuring the level in patients with premature coronary artery disease or patients with hypercholesterolemia resistant to statin medication.
Higher serum phosphorous levels are associated with increased risk of cardiovascular disease in individuals with normal renal function, based on data gathered prospectively in 3368 Framingham Offspring study participants (Arch Intern Med. 2007. 167. 879-885 and editorial 873-874).
This measures lipoprotein phospholipase A2, a compound which occurs only within blood vessels.
Levels below 200 ng/ml are optimal; levels above 250 ng/ml indicate a high risk of plaque rupture.
RDW (red cell distribution width)
This objective measure of heterogeneity in red blood cell size is a powerful independent predictor of future CHD risk, based on data in 7556 participants in NHANES 1999-2006; higher RDW associated with increased risk (Am J Cardiol. 2010. 106. 988-993).
NOTE high RDW is also predictive of morbidity and mortality in those with CHF, MI, and stable coronary artery disease (Eur J Heart Fail. 2010. 12. 129-136; Am J Cardiol. 2010. 105. 312-317; Arch Intern Med. 2009. 169. 515-523; Circulation. 2008. 117. 163-168).
Triglycerides are fat-like substances in the blood.
More than 30 prospective studies involving more than 250,000 participants have demonstrated a correlation between high fasting triglyceride level and higher risk of heart disease, even after controlling for other risk factors (Curr Atheroscler Rep. 2008. 10 386-390).
Nonfasting triglycerides are also associated with an increased risk of heart disease
In a prospective cohort study of 26,509 initially healthy US women participating in the Women’s Health Study, at median follow up of 11.4 years, nonfasting triglyceride levels were associated with incident cardiovascular events, independent of traditional risk factors, whereas fasting triglyceride levels showed little independent relationship (JAMA. 2007. 298. 309-316).
Nonfasting triglyceride level will vary as a function of hour many hours it is drawn postprandially, so while cohort studies show the value of a nonfasting level, applying this data to individuals may require standardization such that the level is drawn 2 hours postprandial, and this can be logistically challenging in the individual (Editorial. JAMA. 2007. 298. 336-338).
While fasting and nonfasting triglyceride levels are correlated with an increased risk of heart disease, these elevations are also correlated with low HDL cholesterol, and with small, dense LDL, so it is not clear whether high triglycerides are truly an independent risk factor for heart disease versus a risk marker for heart disease (Editorial. JAMA. 2007. 298. 336-338).
Optimal triglyceride level is < 150 mg/dl and acceptable triglyceride level is < 200 mg/dl. Data for 5610 participants in NHANES 199-2004 shows that 1/3 have a triglyceride level >150 mg/dl and 1/5 have a triglyceride level > 200 mg/dl (Arch Intern Med. 2009. 169. 572-578).
Treatment for high triglycerides
Alcohol in moderation – excess alcohol can cause very high triglyceride levels.
Blood sugar control – uncontrolled diabetes can cause very high triglyceride levels.
Exercise – both aerobic and resistance exercises are beneficial
Nutrition – reduce intake of high-fructose corn synrup, and reduce intake of high glycemic index foods (i.e. pretzels, bagels, breakfast cereals)
CLA 750 mg twice a day - this omega 9 fatty acid has been reported to decrease triglycerides
Niacin - no effect on cardiovascular mortality, noncardiovascular mortality, or total mortality, based on a meta-analysis (Arch Intern Med. 2005. 165. 725-730).
Omega 3 fats – 2-4 grams of EPA + DHA per day recommended by the American Heart Association.
Vitamin C – recommended by Thomas E Levy (Stop America’s #1 Killer! 2006. Chapter 6).
Statins - lower cardiovascular events, cardiovascular mortality, and total mortality.
Fish oil – prescription Lovaza or Vascepa
Fibrates - decrease risk of cardiovascular events, but increase noncardiovascular mortality, and no documented benefit in 2009 with regard to cardiovascular mortality or total mortality.
Metformin – off-label use
Hyperuricemia (uric acid > 7.0 mg/dl in men and > 6.5 mg/dl in women) is a risk marker for cardiovascular disease, hypertension, kidney disease, metabolic syndrome, and obesity (Hypertension. 2005. 45. 18-20). Preliminary data suggests that uric acid is a risk factor, not just merely a risk marker.
Uric acid is an antioxidant.
Fructose is the only sugar that raises uric acid levels (Ann Rheum Disease. 1974. 33. 276-280).
Uric acid levels in the U.S. have steadily increased over the past 60 years, possibly due to increased fructose in the diet.
Excellent summary article in Cleveland Clinic Journal of Medicine. 2006. 73. 1059-1064.
WBC (white blood cell count)
Risk marker for coronary artery disease, based on data gathered in 2208 patients in the TACTICS-TIMI 18 trial (J Am Coll Cardiol. 2002. 40. 1761-1768).
Specifically, based on a study in which 3227 consecutive patients without a MI who had baseline angiography and were followed prospectively, a high neutrophil count and a low lymphocyte count were predictive of risk of MI and death (J Am Coll Cardiol. 2005. 45. 1638-1643).
Hypothetical mechanism – elevations occur in conjunction with inflammation.
Page Updated December 2, 2018