Cholesterol, Lipids and Treatments, including statins

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Introduction

If you haven't already read the Lipids section of the Primer, please do so first. We're assuming you know a little about the different kinds of lipids, including cholesterol and triglycerides, and how they differ from what we eat, like saturated fats.

We know that E4 carriers are at higher risk of cardiovascular disease (CVD) and they also tend to have higher circulating levels of lipoproteins such as LDL cholesterol. E4 is the ancestral allele, and in ancient man, there were two important benefits of higher levels of lipoproteins.

  • Lipoproteins are part of the innate immune system. Circulating lipoproteins, (including HDL, chylomicrons, VLDL, LDL, and Lp(a)), have the ability to bind and neutralize LPS. They bind and neutralize a wide variety of enveloped and nonenveloped DNA and RNA viruses and protect from certain parasitic infections (Khovidhunkit, W., et al, 2004). As an ancestral allele, higher levels of lipoproteins would have been protective against infection and critical to survival in a time of no antibiotics or medical treatment.
  • Because ApoE4 is associated with both a higher absorption of cholesterol at intestinal level, and higher plasma cholesterol levels, this allele could help in rebalancing cholesterol levels which would otherwise be too low in circumstances where the food supply was scarce, sporadically available, or qualitatively poor. (Corbo, R., and Scacchi, R., 1999)

About 80-85% of cholesterol is made in the liver. Cholesterol derived from our food usually has minimal effect on our blood levels of cholesterol. But, given that E4s tend to have higher baseline levels, it is important to untangle how the science has progressed from "eat low fat" to an understanding that the onset of cardiovascular disease (CVD) is much more nuanced than just high circulating cholesterol.

Why understanding lipids is important for ApoE4s

E3/E4 and E4/E4s have a higher risk of coronary heart disease than other genotypes. (Min Xu, et al., 2016) And, in general, E4 carriers tend to have higher levels of circulating LDL due to the poor transport capability of the ApoE4 protein. But it's not as clear how high is too high. And the solution to high LDL? Well, it's complicated. Read any given article on any given day and you might see clinicians, researchers, and bloggers touting "low-fat diets", "insulin resistance trumps all", "a high-fat diet won't kill you" or "statins for all" strategies. It's frustrating and difficult to know what's right when our personal health is on the line.


Lipids and Alzheimer's Disease

Of course, our long-term goal is to avoid Alzheimer's. There may be some links to lipids, but it might be too simplistic to say high cholesterol is bad and statins will save your brain. For a good review of the issues, see this discussion debating cholesterol as a causative factor, (Wood, W.G., et all, 2014). Here are some recent research studies that look at the specifics of the relationship of lipids and AD.

  • "Increased levels of triglycerides at midlife predict brain Aβ and tau pathology 20 years later in cognitively healthy individuals. Certain lipoprotein subfractions may also be risk factors for Aβ pathology. These findings further support an involvement of lipids in the very early stages of AD development." (Nägga K, et al, 2017)
  • "High total cholesterol in middle age and low total cholesterol in later life are associated with an increased risk of dementia showing a U-shaped relationship." (Abdelhafiz AH, et al, 2012)
  • A longitudinal study of people born in the early 1930s also found the that participants with MCI and AD in their 70s (referred to as their time point VT3) had higher TC levels in their early 60s than those who were healthy. "Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications." (Toro P., et al, 2014)
  • "Converging evidence from clinical and pathological studies indicate the presence of important relationships between the ongoing deterioration of brain lipid homeostasis, vascular changes and the pathophysiology of sporadic Alzheimer's disease (AD). These associations include the recognition of cholesterol transporters apolipoprotein E (APOE), APOC1 and APOJ as major genetic risk factors for common AD and observations associating risk factors for cardiovascular disease such as high midlife plasma cholesterol, diabetes, stroke, obesity and hypertension to dementia. Moreover, recent clinical findings lend support to the notion that progressive deterioration of cholesterol homeostasis in AD is a central player in the disease pathophysiology and is, therefore, a potential therapeutic target for disease prevention." (Leduc, V., et al, 2010)

Lipids, CAD and Mortality

Mortality is a good end point to watch in studies, because if we die of CVD before we reach an age where AD onset is a problem, then we haven't really addressed all the important factors of good health. Results from research in the 1990s that looked at statin use led to the cholesterol theory that lowering cholesterol would decrease cardiac mortality and increase life expectancy. In 1994, the Scandinavian Simvastatin Survival Study (4S), found that over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, and improved survival in CHD patients. (Lancet Scandinavian Simvastatin Survival Study Group, 1994)


Today, patients with high levels of LDL-C are still considered at increased risk of cardiovascular disease, and lowering LDL-C using statins is still the primary treatment to reduce risk of CAD. (American Colllege of Cardiology) While LDL-C reduction does lead to significantly decreased risk of cardiovascular events, there are still a substantial number of patients who have cardiovascular events despite adequate control of LDL-C. (New England Journal of Medicine Study Group, 1998; Lancet Heart Protection Study Collaborative Group, 2002; Shepherd J., et al, 1995; Downs, J., et al, 1998)


Over time, other research started to challenge the cholesterol theory by noting that association is not the same as causation.

  • "However, if one examines the original Framingham Heart Study data (as an example) it is clear that the cholesterol levels of those who developed CHD and those who did not overlap except when the total cholesterol level exceeded 380 mg/dL or was less than 150 mg/dL (Figure ​(Figure1).1). Moreover, cholesterol may be associated with CHD but that does not prove causation." (DuBroff, R. and de Lorgeril, M., 2015)


Some newer research found that some of the old estimation models were biased.

  • "There is an intense debate as to whether the recommended target levels from the lipid- lowering guidelines provide a survival difference in primary prevention. More than 50% of the population aged 50 + have levels above the recommended levels. (Bathum, L., et al, 2013)
    • This study indicates that high total, HDL-, or LDL-cholesterol in those aged 50 + years free from CVD or diabetes at baseline are associated with lower all-cause mortality.
    • However, cholesterol-lowering treatment in the form of statins provides a survival benefit without correlation to cholesterol level.
    • High triglyceride levels were found to be associated with higher all-cause mortality, which was most pronounced in women."
  • "Among women, serum cholesterol had an inverse association with all-cause mortality as well as CVD mortality (although not reaching statistical significance)...Among men, cholesterol did not seem to be linearly associated with mortality but rather the association followed a U-shaped pattern, with the lowest mortality appearing in the second cholesterol category (5.0–5.9 mmol L−1)...Consequently, cholesterol analysed as a continuous variable did not show a statistically significant linear association with mortality." (Petursson, H. , et al, 2012)
  • "All-cause mortality is the most appropriate outcome to use when investigating risk factors for life threatening disease. Section 1 discusses all-cause mortality according to cholesterol levels, as determined by large epidemiological studies in Japan. Overall, an inverse trend is found between all-cause mortality and total (or low density lipoprotein - LDL) cholesterol levels: mortality is highest in the lowest cholesterol group without exception. If limited to elderly people, this trend is universal. As discussed in Section 2, elderly people with the highest cholesterol levels have the highest survival rates irrespective of where they live in the world." (S. Karger AG, 2015)


Finally, there is recent research suggesting it is the high variability of total cholesterol between doctor visits that might be a better marker for overall health risks.

  • "There was a linear association between higher TC variability and outcome measures. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest vs. lowest quartiles of CV of TC were 1.26 (1.24-1.28) for all-cause mortality, 1.08 (1.05-1.11) for MI, and 1.11 (1.08-1.14) for stroke, which was independent of mean TC levels and the use of lipid-lowering agents." (Kim, M.K., et al, 2017)

Know and rule out other causes

This is important. Some physicians will look at typical E4 lipid panel results, see the high total cholesterol, and immediately talk to you about being on a statin. Statins certainly have a role in controlling high cholesterol, but as a rule, it's good to investigate and rule out or treat other causes of CVD. Because there are many factors that influence lipid panel results, it's important to know which factors might be driving those results. Simply driving down cholesterol might not bring protection from CVD if factors like insulin resistance, chronic inflammation and obesity are not addressed. For example, insulin resistance, as measured by HOMA-IR, appears to be independently associated with greater risk of cardiovascular or all-cause mortality in non-diabetic adults, so insulin resistance is one risk factor we can control. (Zhang X., et al., 2017)


A word to the wise

So before we dig into the details, here's an important reminder from our Primer and Dr. Stavia: The field of lipids (called lipidology) is very complex and still somewhat controversial. The science is not settled, and it is certainly not black and white. The tendency of the press and doctors to oversimplify gives the false dichotomy of good versus bad. Lipids are very complex and nuanced and digging deeper, the impression that high is bad and low is good, is totally false. However, there is no controversy that high triglycerides, as measured on a lipid panel, are detrimental. The controversy and the unknowns are in the field of the LDL and LDL-subparticles.

Lipid panels and deciphering the alphabet soup

Acronyms you'll see in the research

  • ω-3 PUFA - omega-3 polyunsaturated fatty acid
  • ω-6 PUFA - omega-6 polyunsaturated fatty acid
  • CAD - coronary artery disease (where plaque builds up inside the coronary arteries, leading to atherosclerosis)
  • CHD - coronary heart disease (aka, CAD, IHD)
  • CHO - carbohydrate
  • CVD - cardiovascular disease (refers to heart and blood vessel diseases, including heart attacks, strokes, arrhythmias and other heart related diseases)
  • FA - fatty acids
  • HDL - high density lipoprotein
  • IHD - ischemic heart disease (aka, CAD, CHD)
  • LDL - low density lipoprotein
  • Lp(a) - Lipoprotein(a), a proatherogenic and prothrombotic lipoprotein
  • MetS - metabolic syndrome
  • oxLDL - oxidized low density lipoprotein
  • sdLDL - small dense low density lipoprotein
  • SFA - saturated fatty acid
  • TG - triglycerides
  • VLDL - very low density lipoprotein


Testing lipids: which tests and ratios are helpful

What are "healthy" levels of lipids? This is a tough nut to crack. Opinions are all over the board. We do know that high levels of oxLDL or sdLDL are associated with increased risk of CAD. There are important outstanding questions about high LDL-P that haven't been answered, like is high LDL-P okay in the presence of low glycemic markers, low levels of inflammation, and a generally healthy lifestyle? Our best advice is to work with your doctor to control any health issues such as insulin resistance, hormonal levels and stress, add regular exercise, lose weight and tweak your diet while watching the impact on your lipid results.

This section will concentrate on some basic labs and a few advanced tests that can help you figure out or track your markers related to good heart health. There are other advanced tests available, but these represent a good place to start.


Basic lipid panels: Triglycerides, Total cholesterol, HDL-C, LDL-C (calculated), and most times you will get a non-HDL cholesterol (calculated) and Cholesterol/HDL Ratio (calculated) results. You should be able to get a basic lipid panel ordered through any doctor's office, or find a direct-to-consumer option like Walk-In Lab or Life Extension(this includes some advanced tests, too).


Oxidation tests: sdLDL (can be ordered without doctor, such as Life Extension) or oxLDL (another test you can self-order, such as Life Extension).


Other important markers to test are related to inflammation and insulin resistance: hs-CRP (inflammation), homocysteine, HbA1c and fasting insulin. These can also be ordered through any doctor's office, or a direct-to-consumer option like Walk-In Lab or Life Extension.


Advanced tests including lipid subparticles - see below about interpreting subparticles:

  • ApoA-I. "Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events." (Mani, P., et al, 2015)
  • ApoB. A true measure of concentrations of atherogenic lipoproteins such as LDL and the smaller varieties of VLDL. This study found that predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements.
  • Lp(a). "About 20% or one in five people have high levels of Lp(a) greater than 50mg/dL from birth based on genetic factors they inherited from their parents, and most don’t know they have it. As high levels of Lp(a) travel through the bloodstream, it collects in the arteries, leading to gradual narrowing of the artery that can limit blood supply to the heart, brain, and kidneys as well as the legs. It can increase the risk of blood clots, heart attack or stroke." (lipoproteinafoundation.org)
  • LPIR. LPIR (Lipoprotein insulin resistance) is a weighted score of VLDL, LDL, and HDL particle sizes, and large VLDL, small LDL, and large HDL particle concentrations that are more strongly related to insulin resistance than each of its individual subclasses. (Harada, P., et al, 2017)

Cardio risk panels

  • Labcorp offers: NMR LipoProfile - historical graph (LDL-P, LDL-C); insulin-resistance score; lipoprotein particle number (LDL-P); particle concentration and size (total HDL-P, small LDL-P, LDL size); standard lipid panel (total cholesterol, calculated LDL cholesterol, HDL cholesterol, triglycerides)
  • Quest offers: Cardio IQ Panel - Basic Lipid Panels, Lipoprotein Subfractionation, Apolipoproteins, Inflammation Biomarkers, Heart Failure, Metabolic Markers, Genetic Cardiovascular Markers


Pay attention to:

  • Triglyceride/HDL-C ratio. A high ratio of triglycerides to HDL (TG/HDL-C) predicts extensive coronary disease in both men and women. (Lamoz da Luz, P., et al, 2008) The ratio correlates inversely with the plasma level of small, dense LDL particles. Hanak, V., et al, found 79% of subjects with type B pattern (small, dense LDL) had values over 3.8, but 81% showed type A pattern (large, fluffy) if below 3.8. Dr. Steven Gundry suggests you should target < 1.0.
  • sdLDL-C (< 30 mg/dL) and oxLDL (< 60 - U/L), per Dr. Steven Gundry. Dr. Bredesen suggests a sdLDL-C < 20. "Relative to larger LDL particles, sdLDL particles are less easily cleared from the circulation due to reduced receptor-mediated uptake and thus have a longer intravascular residence time. Additional mechanisms by which sdLDL may have relatively greater atherogenic potential than larger LDL include their higher affinity for binding to proteoglycans and increased susceptibility to oxidation, resulting in greater arterial retention and capacity to trigger inflammatory processes." (Siri-Tarino, P.W., et al, 2015).
  • Insulin resistance. HbA1c should be <5.6 and fasting insulin <= 5.4 ulU/mL per Dr. Bredesen and Dr. Stavia recommends an HbA1c closer to 5. A good score for LPIR is < 27.
  • Inflammation. hs-CRP < 0.9 mg/dL per Dr. Bredesen.
  • Homocysteine. <=6 umol/L per Dr. Bredesen.
  • HDL-C. 60 mg/dL or greater is considered as best for preventing CHD. (Medline) But, not too high, because high levels are associated with high mortality. (Madsen, CM, et al, 2017)
  • ApoB/ApoA-I ratio. The lower the apoB/apoA-I ratio, the lower is the risk. (Walldius G., 2012) Values for men < 0.70 and for females < 0.60 are considered normal especially if no other risk factors are present. Values of the apo-ratio> 0.90 show a considerable increase in risk.
  • Lp(a). A normal level is less than 30 mg/dL or less than 75 nmols/L. Levels higher than this are associated with an increased risk of heart attack, stroke, or narrowed arteries supplying blood to vital organs, often at an early age (younger than 55 in men and 65 in women). (lipoproteinafoundation.org)


Evidence is not as clear for TC and LDL-C, unless you are diagnosed with hypercholesterolemia:

  • Total cholesterol and LDL-C. Lamez da Luz, P., et al (2008) found that the relationship was not significant between extent of coronary disease and total cholesterol [1.25 (0.82–1.91; p = 0.33)] or LDL-c [1.47 (0.96–2.25; p = 0.0842)].
  • However, even recently, Varbo, A., et al (2013) found that "Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation."
  • So, many members do try to keep their lipids as close to "normal" ranges as possible by concentrating on eating "healthy" fats such as olive oil and avocados and limiting saturated fats, and if necessary, further reductions with supplements and medication.


And most importantly, don't let your total cholesterol get too low. Dr. Bredesen recommends >150 mg/dL to avoid brain atrophy.


Interpreting LDL Particle Number (LDL-P) and other lipid subparticles through advanced lipid tests

Research initially suggested that LDL-P and knowing your "Pattern" (A, large fluffy LDL and B, small dense LDL) were important in treating CVD. Over time, research started to show that both small and large LDL share atherogenic properties. Advanced lipid tests are useful for diagnosing certain dyslipidemias and for individuals whose LDL-C is discordant with LDL-P or ApoB (LDL-C is high and LDL-P or ApoB low OR LDL-C is low and LDL-P or ApoB high).

In addition, one area where knowing your small LDL-P will be critical is if you have been diagnosed with diabetes. For an overview of how lipid subparticles stack up in diagnosis, check out this slide set from Brigham and Women's Hospital. Our best advice for interpreting advanced lipid test results is to work with a lipidologist or cardiologist, preferably one familiar with ApoE4.


If your tests show markers well out of range, you might also consider a Coronary Calcium Scan to see if you have calcified plaque, at which point you will want to aggressively root out your specific health issues that might contribute to the score.


Strategies

Here are some suggestions to maintaining healthy lipids, synthesized from research, our blog threads and other sources (for more details head to the deeper dive section).


Reduce oxidized LDL (sdLDL, oxLDL)

  • Dietary carbohydrates, as well as excess calories, have been shown to increase hepatic TG stores, and ultimately raise sdLDL. (Siri-Tarino, P.W., et al, 2015).
  • Avoiding saturated fats (including coconut oil), eating more fiber and avoiding refined sugar and carbohydrates can help lower these numbers. (Moll, 2017)
  • Rule out H. pylori infection. "More serious coronary atherosclerosis was observed in CHD patients with H. pylori +CagA+ infection. H. pylori +CagA+ infection might be involved in coronary atherosclerosis by modifying serum lipids, enhancing LDL oxidation, and activating the inflammatory responses." (Huang B., et al, 2001)


Control insulin resistance

Triglycerides, Triglyceride/HDL ratio and sdLDL levels should drop with lower carbohydrate intake, especially by eliminating sugar and refined carbohydrates. See more information on the insulin resistance page.


Control inflammation

Know your inflammatory markers and treat the underlying cause. Because this could be a wiki post on its own due to the many things can contribute to inflammation including periodontal disease, autoimmune disease, and obesity, we'll just underscore the link between markers and CAD. Even mild elevation of hs-CRP is associated with higher risk independent of of other risk factors. It will be critical to work with your doctor to figure out why your inflammatory markers are high.

  • "It is widely recognized that atherosclerosis is an inflammatory disorder [1]. Moreover, recent epidemiological studies have strongly suggested that disorders that lead to systemic inflammation increase the risk of developing cardiovascular disease. For example, studies have shown that patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, or psoriasis have an increased risk of coronary artery disease [[2], [3], [4], [5]]. Similarly, studies have also suggested that patients with chronic infections such as periodontitis, bronchitis, or HIV infection also appear to be at increased risk of atherosclerosis [[6], [7], [8]]. Furthermore, a number of clinical disorders that are well recognized to increase the risk of cardiovascular disease, such as diabetes, chronic renal failure, and obesity, are now recognized to induce systemic inflammation [[9], [10]]." (Feingold, K., et al, 2007)


Treat infections, including "leaky gut"

Inflammation from infections can cause profound alterations in lipid metabolism and to the composition of lipoprotein subclasses.

  • H. pylori infection is associated with lower HDL and higher triglyceride levels. (Sun Y, et al, 2016)
  • "...the level of C pneumoniae and H pylori-specific IgG antibodies are elevated among CAD patients and their presence was associated with development of the disease. They were significantly correlated to cholesterol level." (Al-Ghamdi A., et al, 2011)
  • "Leaky gut" is now being studied for its association with many chronic diseases. Definitely worth treating, and certainly an area of research to watch. "The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride-rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis." (Fändriks L., 2017)

Reduce homocysteine

See our post on Hacking Homocysteine for ideas.


Change your diet

No trans fats. I'm assuming we don't need to chat about avoiding trans fats. If you are still eating them, just stop, please!

Substitute "healthy" fats, like extra virgin olive oil and nuts, for saturated or polyunsaturated fats. Analysis from the PREDIMED study showed that higher baseline total olive oil consumption was associated with 48% reduced risk of cardiovascular mortality, and for each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. They also found inverse associations between olive oil consumption and CVD not only in the group supplemented with EVOO but also in the group supplemented with nuts.(Guasch-Ferré M, et al, 2014)

Eat more fiber. This meta-analysis of cohort studies shows that fruit and vegetable consumption is inversely associated with the risk of CHD. (Dauchet, L., et al, 2006) And a systematic analysis of 10 cohort studies from the United States and Europe showed that results were similar for both men and women. (Pereira, M., et al, 2004)

Lower your carbohydrate intake. Carbohydrates drive triglyceride levels, and you can reduce triglycerides by eliminating sugar and refined carbohydrates, as well as reducing overall carbohydrate intake. See more information on the insulin resistance page.

But also keep in mind:

  • The effects of diet and macronutrient replacements on CVD risk are mediated by numerous physiological factors, including lipids and lipoproteins, inflammation, insulin sensitivity, blood pressure (BP), thrombosis, and vascular function. (Siri-Tarino, P.W., et al, 2015).

Reduce saturated fat in the diet

Saturated fats effects on CVD is generally clear as mud. For most people, saturated fats do tend to drive LDL higher, especially in E4s.

  • SFAs may increase CRP in E4s. "We provide novel evidence of a divergent CRP response to SFA according to APOE genotype, with a significant increase in CRP concentrations after increased SFA intakes evident only in APOE4 carriers." (Carvalho-Wells, A., et al, 2012)
  • Dr. Gundry, a cardiologist with whom some of our members consult, does not recommend saturated fats, like coconut oil or animal fats, for his E4 patients because they tend to raise sdLDL.
  • Dr. Bredesen thinks coconut oil and preferably MCT oil can be very helpful for E4 carriers who are exhibiting symptoms of cognitive decline as it can address a reduction in cerebral glucose utilization inherent to our gene, which is exacerbated with insulin resistance, menopause, and age. As cognition and glycemic markers improve, he suggests maintaining mild levels of ketosis, but moving away from SFA and using traditional Mediterranean fats instead: high polyphenol EVOO, olives, nuts, seeds, avocados.
  • If you are Insulin Resistant or have Type 2 Diabetes, the advice about saturated fats is different and you absolutely should reduce saturated fat intake. In metabolic studies, saturated fat impairs insulin sensitivity and unsaturated fat improves glucose metabolism. (Lichtenstein AH1, Schwab US., 2000, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532752/) Replacing saturated fat with monounsaturated fat improves lipoprotein and glycemic control in those with type 2 diabetes.

If you want to see more about what the research says, check out the deeper dive section.

Treat thyroid problems

Hypothyroidism may cause a slow heart rate, a rise in cholesterol, an increase in fluid around the heart, and heart failure. (Harvard Health Publishing) A precursor to hypothyroidism called subclinical hypothyroidism may cause some changes in the blood fats and blood vessel function that may lead to an increased risk of narrowing of the arteries. This report from the Harvard Medical School suggests, "If your TSH level is elevated to between 4.5 and 10 mIU/L and your T4 is normal, you should be considered for treatment with thyroid medication, especially if you have symptoms of hypothyroidism, or you have a positive test for thyroid antibodies, a history of heart disease, or risk factors for atherosclerosis."


Lose weight

Yep, you just have to do it. A recent review of data from Asia, Australia and New Zealand, Europe, and North America showed associations with being overweight or obesity and higher all-cause mortality, and it was consistent across all populations. (The Global BMI Mortality Collaboration, 2016) See also: (Yoo, B., et al, 2017; Hou, X., et al, 2013)

Shoot for a BMI in normal ranges. Here is one BMI calculator that works for standard or metric measures.

Look at other known CHD factors

If you smoke, stop.

  • "In contrast to cholesterol, the detrimental effect of smoking was clearly evident even after stratifying for cholesterol levels (Table 3). This emphasizes the importance of smoking as a CVD risk factor compared with cholesterol." (Petursson, H., et al, 2012) And many more studies emphasize the high risk of smoking.

Control hypertension. Besides using pharmaceuticals, also consider:

  • Treating MTHFR, a known factor for high blood pressure. It can raise risk of hypertension by 24-87%. (McNulty, H., et al, 2017)
  • Trying yoga. A number of randomized controlled trials found an overall effect of about 10 mmHg reduction in systolic and about 8 mmHg reduction in diastolic blood pressure. (Cramer, H., 2016)
  • Treating sleep apnea. "OSA [obstructive sleep apnea] plus HTN [hypertension] is associated with prevalent CVD, and OSA may potentiate the adverse cardiovascular effects on hypertensives patients but not normotensives." (Wang, L., et al, 2016)

Decrease your stress levels.

Get up and move.

  • "Exercise is a key component in the treatment of patients with the MetS and in the prevention of CVD morbidity and mortality. The results of this study are in line with previous meta-analyses and extensive reviews that focused on the effect of exercise on single risk factors in populations with different cardiovascular risk factors [4–7]." (Pattyn, N., et al, 2013)


Take statins

Statins are either the savior of heart disease or the devil incarnate. Please note, this is a discussion you must have with your doctor. We highly recommend finding a doctor or cardiologist familiar with ApoE4 and it's effects. If you decide to take a statin, look for choices that do not cross the blood-brain-barrier. Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic. Lipophilic statins cross the blood-brain barrier more readily and may cause brain side effects like brain fog. Also consider taking CoQ10 to avoid muscle and joint pain. Please check out the deeper dive section that includes information from the 2014 American College of Cardiology Guidelines, with which most physicians will be familiar.


Overall, the Cochrane Database Review, Statins for the primary prevention of cardiovascular disease. (Taylor F, et al, 2013), noted:

  • "Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event."

A 2016 review of Medline and Cochrane studies also found similar benefits. (Chou R., et al, 2016)

  • "In adults at increased CVD risk but without prior CVD events, statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and CVD events, with greater absolute benefits in patients at greater baseline risk."


Newer research does show that if you have high variability in your total cholesterol from lab test to lab test, (which may indicate increased health risk) (Kim, M.K., et al, 2017) then statins may provide a protective benefit from coronary events, death, myocardial infarction, or stroke (Bangalore, S., et al , 2015).


And once again, don't let your total cholesterol get too low. Dr. Bredesen recommends >150 mg/dL to avoid brain atrophy.

Use other lipid altering drugs/supplements

First up is a general review of non-statin therapies from 2015, followed by background on other forms of therapies. Like statins, this is a conversation you must have with your doctor to know what is going to work for your situation.

Nonstatin therapies for management of dyslipidemia: a review. (Sando KR, Knight M, 2015)

  • "Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome."


Ezetimibe (Zetia)

  • How it works. Ezetimibe is a cholesterol absorption inhibitor, which blocks the amount of cholesterol that’s absorbed from your intestines.
  • "Depending on atorvastatin dose, this combination provides LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and high-density lipoprotein cholesterol (HDL-C) increases of 5-9%. Studies comparing the lipid-lowering efficacy of the atorvastatin-ezetimibe combination with the alternatives of statin dose titration or switching to a more potent statin consistently showed that combination therapy provided greater LDL-C reduction, translating into a greater proportion of patients achieving lipid goals. Simvastatin-ezetimibe combinations have been shown to reduce the incidence of major atherosclerotic events in several clinical settings to a magnitude that seems similar to that observed with statins for the same degree of absolute LDL-C lowering. The atorvastatin-ezetimibe combination has also been shown to induce the regression of coronary atherosclerosis measured by intravascular ultrasound in a significantly greater proportion of patients than atorvastatin alone." (Ferreira, A.M., et al, 2017)
  • "The recently published IMPROVE-IT study is the first to prove that the addition of ezetimibe as a non-statin type drug, to statin treatment contributes to further reduction of LDL-cholesterol. The combination treatment results in additional decrease in the incidence and mortality of cerebrovascular events, without any expansion in the number or adverse effects." (Lovadi E., et al, 2016)
  • This drug evaluation also stated that ezetimibe and simvastatin was appropriate for "subjects with high cardiovascular risk who need to optimize their LDL-Cholesterolemia, but also in patients who cannot tolerate high-dose of more powerful statins."
  • And lastly, "The ApoE genotype does not predict the efficacy of ezetimibe treatment on serum lipid parameters." (Harangi M., et al, 2013)


Bile acid sequestrants

  • How they work. "Bile acid sequestrants bind bile acids in the intestine and increase the excretion of bile acids in the stool. This reduces the amount of bile acids returning to the liver and forces the liver to produce more bile acids to replace the bile acids lost in the stool. In order to produce more bile acids, the liver converts more cholesterol into bile acids, which lowers the level of cholesterol in the blood." (MedicineNet.com)
  • Examples of these include cholestyramine (Locholest), colesevelam (Welchol), or colestipol (Colestid). These are typically prescribed as an adjunct therapy if statins fail to lower lipids sufficiently, or as a replacement therapy in the case of statin side effects.
  • A meta-analysis of prospective studies suggested "that therapy with BAS significantly improves HDL-C, LDL-C, and glycemic markers including fasting blood glucose, HbA1c levels, while deteriorating triglyceride levels." (Mazidi M., et al, 2017)
  • However, "Bile acid sequestrants can be difficult to use as they decrease the absorption of multiple drugs, increase triglyceride levels, and cause constipation and other GI side effects." (Feingold, K. and Grunfeld, C., 2016)
  • These drugs may also be used for glycemic control in type 2 diabetes management by lowering HbA1c results. (Hansen M., et al, 2017)


PCSK9 inhibitors

  • How they work. "We all have a gene called proprotein convertase subtilisin/kexin type 9 (PCSK9). This gene directly affects the number of low-density lipoprotein (LDL) receptors in the body. LDL receptors help regulate the amount of LDL cholesterol that enters the bloodstream. Most LDL receptors are found on the surface of the liver...PCSK9 drugs suppress the PCSK9 enzyme expressed by the gene." (HealthLine.com)
  • "Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population." (Koskinas K.C., et al, 2017)
  • "...studies were performed in patients affected by homozygous or heterozygous familial hypercholesterolemia, or with increased cardiovascular risk, two in patients with statin intolerance, three in statin-naïve patients, and 10 in patients unable to achieve LDL-C target with statin therapy...PCSK9 inhibitors reduce LDL-C concentration in every group explored. A significant reduction in death by all cause was observed in the PCSK9 inhibitors groups, compared with control groups, even in the short time frame studied. (Squizzato A., et al, 2017)
  • A 2017 Cochrane Database review noted, "Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%)."
  • And before you settle on PCSK9 inhibitors, please read this cautionary paper that "we are far from fully understanding the physiological role of this protein: a number of experimental and some clinical data suggest that PCSK9 may not serve only the role of controlling plasma cholesterol." (Norata, G., et al, 2016)


Fibrates

  • How they work. All of the fibrates work via activation of the nuclear hormone receptor PPAR alpha. This activation lowers blood triglyceride levels by reducing the liver's production of VLDL (the triglyceride-carrying particle that circulates in the blood) and by speeding up the removal of triglycerides from the blood. This also can stimulate apolipoprotein A-I and A-II transcription and increase levels of HDL.
  • "Fibrates reduce triglyceride levels by 25-50% and increase HDL cholesterol levels by 5-20%. The effect on LDL cholesterol is variable. If the triglyceride levels are very high (>400-500mg/dl), fibrate therapy may result in an increase in LDL cholesterol levels, whereas if triglycerides are not markedly elevated fibrates decrease LDL cholesterol by 10-30%. Fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL cholesterol levels and there may be a shift from small dense LDL towards large LDL particles. Fibrates do not have any major effects on Lp(a) levels. Due to increased myopathy the combination of gemfibrozil and statins should be avoided but fenofibrate can be used safely with statins. Monotherapy with fibrates appears to reduce cardiovascular events particularly in patients with high triglyceride and low HDL cholesterol levels. Whether the addition of fibrates to statin therapy will reduce cardiovascular disease is uncertain. In patients with diabetes fibrates appear to slow the progression of microvascular disease." (Feingold, K. and Grunfeld, C., 2017)
  • "Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects." (Jakob T, et al, 2016)


Niacin

  • How it works. "Niacin was the first drug approved to treat dyslipidemia. In 1955, Altschul et al showed that pharmacologic doses of niacin decreased plasma cholesterol levels [5]. Several forms of niacin are available for clinical use. Immediate release niacin has a short duration of action and is typically given two or three times per day with meals, whereas sustained release niacin and extended release niacin are once a day drugs usually given at bedtime. The extended release form of niacin exhibits release rates that are intermediate between immediate release niacin and sustained release niacin [6]. While the effects of the various forms of niacin on plasma lipid levels are similar, the side effect profiles are different. Because of an increased risk of serious liver toxicity with sustained release niacin this preparation is no longer widely used to treat dyslipidemia. Over-the- counter “No flush” niacin is also available but is generally ineffective as a lipid-modifying agent because most of these preparations do not contain active nicotinic acid... Niacin decreases all the pro-atherogenic lipid and lipoprotein particles including total cholesterol, triglycerides (20-50% decrease), LDL cholesterol, and Lp(a) levels. Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant LDL particles. Moreover, niacin increases HDL cholesterol levels. Skin flushing, insulin resistance, and other side effects have limited the use of niacin. Moreover, the enthusiasm for the use of niacin has decreased with the failure of AIM-HIGH and HPS-2 Thrive to show a decrease in cardiovascular events when niacin was added to statin therapy. " (Feingold, K. and Grunfeld, C., 2017)
  • "Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely." (Schandelmaier S, et al, 2017)


Berberine

  • How it works. Berberine "upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation." (Kong, W., et al, 2004) Note, LDLR = LDL receptor.
  • A meta-analysis showed that "administration of berberine produced a significant reduction in total cholesterol (mean difference − 0.61 mmol/L; 95 % confidence interval − 0.83 to − 0.39), triglycerides (mean difference − 0.50 mmol/L; 95 % confidence interval − 0.69 to − 0.31), and low-density lipoprotein cholesterol (mean difference − 0.65 mmol/L; 95 % confidence interval − 0.76 to − 0.54) levels, with a remarkable increase in high-density lipoprotein (mean difference 0.05 mmol/L; 95 % confidence interval 0.02 to 0.09). No serious adverse effects of berberine have been reported. In conclusion, berberine may have beneficial effects in the control of blood lipid levels. However, the efficacy of berberine in treating hyperlipidemia should be further evaluated by more randomized controlled trials in a larger population of patients." (Dong H., et al, 2013)
  • There are questions about its safety. A recent cardiomyocyte (cell) study "showed that berberine, palmatine, berbamine, and oxyberberine were cardiotoxic, which resulted in arrhythmia and cardiac arrest on CMs in a time- and dose-dependent manner." (Zhang M., et al, 2017) Toxicity is also discussed on the forum.
  • Because this is a supplement, do your research to ensure you are buying a quality product. "The average berberine content across the products was found to be 75% ± 25% of the product label claim, with product potency ranging from 33% to 100%. Nine of the 15 tested products (60%) failed to meet the potency standards of 90% to 110% of labeled content claim, as commonly required of pharmaceutical preparations by the U.S. Pharmacopeial Convention. Evaluation of the relationship between product cost and the measured potency failed to demonstrate an association between quality and cost. Variability in product quality may significantly contribute to inconsistencies in the safety and effectiveness of berberine. In addition, the quality of the berberine product cannot be inferred from its cost." (Funk R., et al, 2017)

Lower Lp(a)

"Lipoprotein(a), is a particle in your blood which carries cholesterol, fats and proteins. The amount your body makes is inherited from one or both parents and is determined by the genes passed on from your parent(s) when you are born. It does not change very much during your lifetime except if you are a women, levels increase as the natural estrogen level declines with menopause. Diet and exercise seems to have little to no impact on the lipoprotein(a) level." (lipoproteinafoundation.org) They also write:

  • High Lp(a) is not rare. One in five people globally and 63 million people in the U.S. have high Lp(a) levels, and most do not know they are at risk.
  • High Lp(a) is the strongest, single, inherited risk factor for early coronary artery disease (CAD) and aortic stenosis, or narrowing of the aorta.

Higher Lp(a) also seems to come along with the territory of carrying E4. (Moriarty, P., et al, 2017)


Lipoprotein (a) Foundation says there is no one treatment that works for all patients. They recommend treating all risk factors including insulin resistance, and making lifestyle changes (e.g. exercise, healthy diet, losing weight, etc).

Niacin is a common choice for treating Lp(a). Extended release niacin was found to lower Lp(a) by up to 40%. (Malaguarnera, G., et al, 2017) However, it can worsen glycemic control. (Goldberg, R., et al, 2008)

Alternative treatments might include L-carnitine, which can decrease Lp(a) levels by about 20%, or PCSK-9 inhibitors, which reduce not only LDL-C, apoB-100, but also Lp(a) concentrations in patient with familiarly hypercholesterolemia. For information on these and other options, see Malaguarnera, G., et al (2017).


For lowering Lp(a), Dr. Gundry "recommends niacinimide (500mg or more) as one tool, straight, flush producing niacin as another and 1 g of vitamin C 2x/day from a well absorbed sources as another." (Tincup, on the forums)


Play with fish oil

Fish oil can reduce triglycerides (Feingold, K. and Grunfeld, C., 2017), but there are questions about it's effects on LDL.

  • A 2014 study (N = 136,701) concluded: "In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype." (Harris, W., et al, 2014)
  • However, a 2013 MESA study (N=2340) found: "Borderline significant APOE-EPA interactions were also found for small LDL and mean LDL particle size (pinteraction=0.04, and 0.05 respectively, figures not shown). Specifically, significant positive association between small LDL and EPA, and significant negative association between mean LDL particle size and EPA were found only in the E4 group, but not in E2 or E3 groups." (Liang, S., et al, 2013) If your small LDL levels are too high, try cutting out fish oil (but still eat fish a few times per week).


Understand sterol absorption markers

In the 1990s, plant sterol-ester enriched spreads (e.g. Benecol) became popular as a means to reduce total cholesterol and LDL cholesterol. Since then, their use has come under increased scrutiny and debate with an improved understanding of the mechanisms of uptake, actions, and consequences of phytosterol ingestion.

From Dr. Thomas Dayspring. "The only thing we know is that in general the CV risk is higher in patients with E4 alleles compared to the others. We also know that as a generality those with E4 alleles tend to hyperabsorb sterols (cholesterol and xenosterols). Almost all of the cholesterol one absorbs comes from endogenous cellular production which through various pathways finds its way to the gut lumen (on average half excreted in stool, half reabsorbed). Very little ingested cholesterol gets absorbed (as it is such a tiny component on the intestinal pool of cholesterol that is available for absorption). However in patients with hyperabsorption of cholesterol (including those with E4) dietary phytosterols which can also be atherogenic are hypothetically worsening their risk with a vegan diet if they significantly raise plant phytosterol levels (campesterol and sitosterol)

My advice - Before any diet check absorption/synthesis status: do markers of cholesterol synthesis (desmosterol and or lathosterol) and markers of absorption (campesterol, sitosterol, cholestanol). If one is a hyperabsorber - avoid plant sterol supplements at all costs. If apoB or LDL-P is high consider ezetimibe (Zetia), a cholesterol absorption blocker as part of the therapy. Plant stanols (Benecol) can also be used - unlike plant sterols they are not readily absorbed.

With respect to fat in take - if one wants to choose that for part of a low carb diet or ketogenic diet because they have insulin resistance - one would have to monitor apoB and LDL-P. If they go up, especially if accompanied by increased desmosterol or lathosterol levels (indicating a sat fat induced hyperabsorption of cholesterol) then one could consider reducing saturated fat intake." Dr. Daysprings's response on the forum.


Supplementing with plant sterols to reduce total cholesterol and LDL cholesterol doesn't work for E4 carriers.

  • "...responses to plant sterols vary by ApoE genotype and may be of little value in ApoE4 carriers, who had reductions in serum carotenoid concentrations but not in TC, LDL-C, or ApoB. (Sanchez-Muniz F., et al, 2009)

And mice studies suggest plant sterol supplements lead to endothelial dysfunction and atherogenesis.

  • "We previously observed in apoE−/− mice that a diet supplemented with PSE (equivalent to a commercially available spread) induced endothelial dysfunction and led to an increase in ischaemic stroke size in wild-type mice.13 Moreover, we observed that inhibition of cholesterol absorption by a diet supplementation with PSE was associated with twice the amount of atherosclerotic lesion formation compared with ezetimibe treatment (a drug that reduces both plasma cholesterol and plant sterol levels), despite similar plasma cholesterol levels. Thus, our previous study identified a positive correlation between sterol concentrations and the extent of atherosclerotic lesions. previously observed in apoE−/− mice that a diet supplemented with PSE (equivalent to a commercially available spread) induced endothelial dysfunction and led to an increase in ischaemic stroke size in wild-type mice.13 Moreover, we observed that inhibition of cholesterol absorption by a diet supplementation with PSE was associated with twice the amount of atherosclerotic lesion formation compared with ezetimibe treatment (a drug that reduces both plasma cholesterol and plant sterol levels), despite similar plasma cholesterol levels. Thus, our previous study identified a positive correlation between sterol concentrations and the extent of atherosclerotic lesions." (Weingärtner O., et al, 2011)
  • "Food supplementation with PSE impairs endothelial function, aggravates ischemic brain injury, effects atherogenesis in mice, and leads to increased tissue sterol concentrations in humans. Therefore, prospective studies are warranted that evaluate not only effects on cholesterol reduction, but also on clinical endpoints." (Weingärtner O., et al, 2008)


Upregulate the LDL receptor

  • Extra virgin olive oil and other monounsaturated fats can help upregulate the LDL receptors. Chris Masterjohn, PhD has a good video, What to Do About High Cholesterol. Word of warning, he does have a PhD in Nutritional Science. He notes that the goal is to maintain high lipid receptor activity because it's important to clear LDL from circulation before it oxidizes. Oxidation is where the bad stuff happens.
  • If you are a post-menopausal woman, consider bHRT. "β‐Estradiol upregulates liver low‐density lipoprotein receptor (LDLR), which, in turn, decreases circulating levels of low‐density lipoprotein, which is a risk factor for coronary artery disease." (Starr, A., et al, 2015)


Know your other genetic risks

Although a recent study of  10,578 patients found that "genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk" (Proitsi, P., 2014), there are several genes linked to CVD.

  • MTHFR C677T, or snp rs1801133, the T (or A) allele is associated with higher homocysteine, which is associated with cardiovascular disease. This paper also lists lesser studied snps effecting B12 and B6 levels. If you struggle raising those levels, check out those snps, too.
  • rs5082, the G allele is associated with worse health markers on high saturated fat diet.
  • rs662799, the A allele is associated with higher BMI from diet with more than 30% fat; also related to higher triglycerides and higher risk of heart attack at an earlier age.
  • rs10757278, the G allele shows an increased association for heart attacks, both in general and more specifically in so-called early onset myocardial infarctions
  • "Although LPA variants have been associated with CHD and aortic valve stenosis, four single nucleotide polymorphism (SNPs) in the LPA gene had been associated with plasma Lp(a) levels: rs 10455872, rs 3798220, rs 41272114 and rs 143431368. The rs 3798220 and rs 10455872 single nucleotide polymorphisms (SNPs), which were most strongly associated with Lp(a) levels, were most strongly associated with coronary disease risk." (Malaguarnera, G., et al, 2017)
  • In Promethease, look at the "coronary artery disease" option under "Medical Conditions". You can also check out the 9P21 gene to see where you might have additional risks for CVD.


Read also https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220464/


Other ideas for correcting specific lab markers

Some take-aways from this study (Siri-Tarino, P.W., et al, 2015):

If your goal is reducing LDL-C. “On average, dietary SFAs increase LDL-C concentrations by ~13 mg/dl when they replace 10% of energy as dietary CHOs. Specific SFAs have been shown to exert differing effects, such that in general there are progressive increases in LDL-C with diminishing chain length. Thus, the potency of the LDL-raising effects of individual SFAs are as follows: lauric acid (C12:0) > myristic acid (C14:0) > palmitic acid (C16:0). Lauric acid relative to other SFAs increases HDL-C significantly and thereby reduces the total cholesterol (TC):HDL-C ratio. In contrast, stearic acid (C18:0) generally has a neutral effect on lipid and lipoprotein profiles when replacing CHO.”


If your goal is reducing sdLDL. “SdLDLs have been shown to be reduced with lower CHO intake, and this effect was found to be independent of high versus low dietary SFAs (15% versus ~8% of energy) when CHO intake was limited to 26% of energy.”


If your goal is going from LDL Pattern B to A. “Further, the prevalence of LDL subclass pattern B, a categorical marker for atherogenic dyslipidemia defined by the predominance of sdLDL, has been linearly and positively associated with increasing concentrations of dietary CHOs in randomized controlled clinical trials (RCTs) due to effects of CHO that can occur in as few as three days.”


Be aware of the potential of mixed results of MUFAs. “Replacement of SFAs with monounsaturated fatty acids (MUFAs) or ω-6 PUFAs decreases total, LDL, and HDL-C and decreases the TC:HDL ratio. In the DELTA study, replacing 7% kcal from SFAs with MUFAs versus CHOs led to similar reductions in LDL-C, a lesser reduction in HDL-C, and lack of increase in TG. Similarly, greater reductions in TC and TG concentrations and thus improvements in lipid profiles were observed with MUFAs versus CHOs as a substitution for SFAs at 10% of total energy in the OmniHeart study.

Improvements in serum lipids and lipoproteins, including changes in the TC:HDL-C ratio, are slightly greater with PUFA relative to MUFA replacement of SFAs. Of note, the effects of SFAs on lipids and lipoproteins may be modulated by PUFA availability, such that LDL-C is only increased by SFAs if PUFA intake is below ~5% of energy.”


Increase ω-3 fatty acids. The ω-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to be effective in reducing plasma TG concentrations.

Indeed, there is consistent epidemiological evidence for the association of dietary total long-chain ω-3 PUFAs, derived primarily from fatty fish, with reduced CVD risk… Circulating concentrations of long-chain ω-3 fatty acids, including EPA and DHA, were also associated with reduced CVD [RR = 0.75 (0.62–0.89)] based on 13 studies with 20,809 participants and 4,073 events. The increased consumption of these ω-3 PUFAs can be relatively accurately assessed via blood biomarkers since they cannot be produced endogenously.”


If you tolerate dairy. “In the MESA (Multi-Ethnic Study of Atherosclerosis) study, intake of dairy products as a source of SFAs was inversely associated with CVD whereas intake of red meats was associated with increased CVD after adjustment for demographics, lifestyle, and dietary confounders [n = 5,209 with 316 cases; HR for +5 grams SFA per day: 0.79 (95% CI: 0.68, 0.92) and 1.26 (95% CI: 1.02, 1.54) for dairy and meat, respectively].”


What about red meat? “The increased CVD risk observed with red meat intake as a source of SFA may be a function of other components of red meat, such as heme iron. Replacement of red meat with other major dietary protein sources, i.e., dairy, poultry, fish, or nuts, was associated with a 13% to 30% reduction in CHD risk in the Nurses’ Health Study. A meta-analysis that included 17 prospective cohort and 3 case control studies indicated that adverse effects on CVD were specific to processed versus unprocessed meats. Thus, some aspect of the processing of meat versus the meat itself—e.g., preservation with sodium, nitrites, and phosphates, or cooking or frying methods—may promote CVD.”


Best diet? “Evidence for cardioprotective dietary effects from epidemiological studies and randomized clinical trials is strongest for a Mediterranean diet pattern. Although various definitions exist, Mediterranean diets are generally characterized by high intakes of fruits, nuts, vegetables, whole-grain cereals, and olive oil; with moderate consumption of fish, poultry, and wine; and low intake of dairy, red meats, and sweets. The PREDIMED (PREvención con DIeta MEDiterránea) study (n = 7,447) was a parallel group, multicenter primary prevention trial of high-risk individuals initially free of CVD. Two arms of the three-arm study were assigned to a Mediterranean diet with either extra virgin olive oil or nut supplementation. Relative to the low-fat control arm, both the olive oil supplementation and nut groups had a significantly decreased risk of coronary events, an effect driven by a significantly reduced incidence of stroke [RR: 0.61 (0.44–0.86)].

Of note, a recent prospective cohort study in Finland showed increased CVD risk when SFAs were replaced with MUFAs, suggesting that this macronutrient replacement scenario may not be the cardioprotective component of the Mediterranean diet, in line with previous data conducted in African green monkeys that showed no benefit of replacing SFAs with MUFAs on coronary artery atherosclerosis.”


What about coconut oil? “In a metabolic study, no effects of SFAs (22% versus 10% total energy) derived from coconut oil were observed on LDL-C, TC, or apoB when the polyunsaturated fat:saturated fat (P:S) ratio was kept constant at ~0.15. In contrast, higher P:S ratios, i.e., 1.9 versus 0.14, in the context of diets with 38% of energy from fat, were associated with significantly lower ratios of LDL to HDL. These data suggest that the proportions of fatty acids may be more important in modulating CVD risk than the absolute amount of SFAs and PUFAs per se.”

A deeper dive into the science

Testing and markers

1) LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study – Implications for LDL Management (Cromwell, W., et al, 2007)

  • "In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25th percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively)."

2) Clinical Implications of Discordance Between LDL Cholesterol and LDL Particle Number (Otvos, J., et al, 2011)

  • "LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR [95% CI]) 1.20 [1.08, 1.34] and 1.32 [1.19, 1.47], respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR: 1.45 [1.19, 1.78]) (LDL-C HR: 1.07 [0.88, 1.30])). IMT also tracked with LDL-P rather than LDL-C, i.e., adjusted mean IMT of 958, 932, and 917 μm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (p=0.002) but not LDL-P (p=0.60). For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P."

3) High-density lipoprotein cholesterol efflux capacity is inversely associated with cardiovascular risk: a systematic review and meta-analysis (Qiu, C., et al, 2017)

  • "A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is associated with cardiovascular risk. A key cardioprotective property of HDL is cholesterol efflux capacity (CEC), the ability of HDL to accept cholesterol from macrophages...Results showed that the highest CEC was significantly associated with a reduced risk of cardiovascular events incidents compared to the lowest CEC (RR, 0.56; 95% CI, 0.37 to 0.85; I 2, 89%); the pooled RR of cardiovascular risk for per unit SD increase was 0.87 (95% CI, 0.73 to 1.04; I 2, 67%). Dose-response curve indicated that cardiovascular risk decreased by 39% (RR, 0.61; 95% CI, 0.51 to 0.74) for per unit CEC increase. Similarly, an inverse association was observed between CEC and the prevalence of cardiovascular events (highest vs. lowest, OR, 0.30; 95% CI, 0.17 to 0.5; I 2 = 63%; per unit SD increase, OR, 0.94; 95% CI, 0.90 to 0.98; I 2 = 71%). However, based on the current data, CEC was not significantly associated with all-cause mortality."

4) Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study. (Orozco-Beltran D., et al, 2017)

  • "In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers."

5) oxLDL - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558469/


Oxidized LDL

1) Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction (Abdo, A., et al, 2017)

  • "It is well documented that LDL oxidation plays a key role in promoting lesion development in atherosclerosis via a number of pathways (reviewed [3], [4]). In addition to the well-defined recognition of oxidised LDL (oxLDL) by various scavenger receptors, which leads to the formation of lipid-laden “foam cells”, there is strong evidence to show a role of oxLDL as a mediator of endothelial dysfunction via its action on endothelial nitric oxide synthase (eNOS), which perturbs nitric oxide (NO•) bioavailability both in vitro [5], [6], [7] and ex vivo [8], [9], [10]."


Insulin resistance

Triglycerides are negatively correlated with cognitive function in nondemented aging adults. (Parthasarathy V., et al, 2017)

  • "Triglyceride levels are inversely correlated with executive function in nondemented elderly adults after controlling for age, education, gender, total cholesterol, LDL, ApoE4 status, CDR, and white-matter microstructure. The fact that the effect of triglycerides on cognition was not clearly mediated by vascular risks or cerebrovascular injury raises questions about widely held assumptions of how triglycerides might impact cognition function."


Inflammation

1) Inflammatory biomarkers in coronary artery disease. (Zakynthinos E., Pappa N., 2009)

  • "Current evidence supports that inflammation is a major driving force underlying the initiation of coronary plaques, their unstable progression, and eventual disruption; patients with a more pronounced vascular inflammatory response have a poorer outcome. Biomarkers are generally considered to be proteins or enzymes - measured in serum, plasma, or blood - that provide independent diagnostic and prognostic value by reflecting an underlying disease state. In the case of coronary artery disease (CAD), inflammatory biomarkers, have been extensively investigated; more evidence exists for C-reactive protein (CRP). Using high sensitivity (hs) assays, epidemiologic data demonstrate an association between hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented CAD. Moreover, a series of prospective studies provide consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for cardiovascular events. Yet, the predictive value of hs-CRP is found to be independent of traditional cardiovascular risk factors. Recent studies suggest that, besides CRP, other inflammatory biomarkers such as cytokines [interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], soluble CD40 ligand, serum amyloid A (SAA), selectins (E-selectin, P-selectin), myeloperoxidase (MPO), matrix metalloproteinases (MMPs), cellular adhesion molecules [intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1)], placental growth factor (PlGF) and A(2) phospholipases may have a potential role for the prediction of risk for developing CAD and may correlate with severity of CAD."

2) Dietary Choline and Betaine Intakes and Risk of Cardiovascular Diseases: Review of Epidemiological Evidence (Rajaie, S., and Esmaillzadeh, A., 2011)

  • "With reviewing studied researches on dietary choline and betaine intake and cardiovascular diseases, it can be concluded that the dietary choline and betaine intake had no significant association with incidence of CVD. However, more intakes of these substances were associated with significant reduction of serum inflammatory markers."


Infections

1) ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response (Barlage, S., et al, 2001)

  • HDL has been demonstrated to play an important physiological role in restricting the harmful effects of inflammation and infection. Besides its role in reverse cholesterol transport it mediates clearance of inflammatory mediators such as bacterial lipopolysaccharide or the scavenging of oxidation products, thereby contributing to tissue integrity.

2) Changes in serum lipoprotein pattern induced by acute infections (Sammalkorpi, K., et al, 1988)

  • "The mass concentrations of both low density lipoprotein (LDL) (P < .001) and high density lipoprotein (HDL)2 (P < .002) were reduced during acute infections due to the lowering of their cholesterol, phospholipid, and protein contents. The reduction of LDL cholesterol was maximal at the acute stage of infection (change −15%, P < .001) while the reduction of HDL2 cholesterol was maximal during the convalescence (change −35%, P < .001). During acute infections LDL became triglyceride-enriched (11.8 v 8.6%, P < .0001) but cholesterol-poor (36.6 v 39.3%, P < .0001). The ratio of HDL cholesterol/LDL cholesterol was significantly reduced during the convalescence (0.42 ± 0.15 v 0.53 ± 0.19, P < .0001). The concentrations of apo A-I and apo A-II were decreased during acute infections (changes −22%, P < .001, and −16%, P < .001, respectively). The very low density lipoprotein (VLDL) was 18% higher during the convalescence period than after the recovery due to the elevations of VLDL triglycerides, cholesterol, and phospholipids."

3) LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction (Vreugdenhil, A., et al, 2001)

  • "In the present study, we obtained evidence that LBP circulates in association with apoB-containing lipoproteins in healthy persons and in septic patients. This association is functional, as LBP bound to LDL and VLDL was observed to enhance the LPS-binding capacity of these lipoproteins, a process known to result in protection from the deleterious effects of LPS toxicity."


Saturated fat

Saturated fats effects on CVD is generally clear as mud. So what’s the deal with saturated fats specifically?

Here are some major points from a handful of recent studies.

1) The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease (DiNicolantonio, JJ, et al, 2016)

  • "It is well accepted that saturated fats can raise blood levels of total cholesterol. Since the majority of circulating cholesterol is packaged into LDL, elevated TC reflects elevated LDL."
  • "However, LDL represents a group of particles, and the sum total of all LDL particles, taken together, only modestly increase CV risk."
  • "Another consideration may be particle size and density. Small-dense particles are more susceptible to oxidation and are pro-atherogenic, pro-thrombotic and pro-inflammatory."
  • "A high concentration of small-dense LDL and a low concentration of large buoyant LDL has been associated with greater CHD risk. In the Quebec Cardiovascular Study, there was a 3-fold increase in CHD risk in individuals with small-dense LDL after adjustment for total LDL concentration, and other lipid fractions."
  • "Interestingly, randomized trial data suggests that eating saturated fats can decrease small-dense LDL and increases large buoyant LDL. Consumption of saturated fat may favorably shift LDL proportions to be protective against CHD—although not all literature supports the benign or protective nature of large buoyant LDL."
  • "Regardless, just as LDL is not a single type of particle, saturated fat is not single kind of fat. Saturated fats are a heterogeneous group of compounds; their effects differ based on the specific fatty acids they contain. For example, while the saturated fatty acid (SFA), palmitate, seems to raise levels of LDL, the SFA, stearate, does not."
  • "Although some saturated fats may affect some lipid fractions in ways that could theoretically increase the risk of CHD, a large Swedish population study found no association between fat intake (of any type) and CHD. A review of cohort and case-control studies likewise did not demonstrate a clear role of saturated fats in CHD.94 Moreover, meta-analyses show that there is limited and inconclusive evidence for modification of total or saturated fat on CHD, or CV morbidity or mortality."
  • "As for the effects of reducing consumption of saturated fats, reducing consumption generally means increasing intake of some other dietary component. Replacing saturated fats with other fats like trans-fats or omega-6 polyunsaturated oils has been found to increase all-cause mortality. Replacing saturated fats with whole grains may be beneficial for CHD, while replacing saturated fats with refined carbohydrates does not decrease risk, and may increase risk of non-fatal MI, particularly when the carbohydrates are concentrated sugars."

2) Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies (de Souza, et al, 2015)

  • "Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations."
  • "The analysis of data from the largest prospective study to examine carbohydrate quality, as measured by glycemic index, suggests that replacement of saturated fat with high glycemic index carbohydrate increased the risk of CVD, but replacement with low glycemic index carbohydrate (such as whole fruits, vegetables, pulses, and grains) decreased risk."
  • "In cohort studies that have directly modeled substitution effects, replacement of saturated fat by polyunsaturated fat (with a corresponding increase in polyunsaturated:saturated (P:S) ratio conferred the greatest reduction in risk of CVD; though these studies did not distinguish between n-3 and n-6 fatty acids as the replacement choice."
  • "Replacement of saturated fat with monounsaturated fat or carbohydrate was not associated with significant reduction in CHD risk but was associated with a small increase in risk of non-fatal myocardial infarction."

3) Reduction in saturated fat intake for cardiovascular disease. (Hooper, L., et al, 2015)

  • "We include 15 randomised controlled trials (RCTs) (17 comparisons, ˜59,000 participants), which used a variety of interventions from providing all food to advice on how to reduce saturated fat."
  • "Replacing the energy from saturated fat with polyunsaturated fat appears to be a useful strategy, and replacement with carbohydrate appears less useful, but effects of replacement with monounsaturated fat were unclear due to inclusion of only one small trial. This effect did not appear to alter by study duration, sex or baseline level of cardiovascular risk. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturated fats. The ideal type of unsaturated fat is unclear."

4) Saturated Fats Versus Polyunsaturated Fats Versus Carbohydrates for Cardiovascular Disease Prevention and Treatment (Siri-Tarino, P.W., et al, 2015)

  • "In summary, most epidemiological studies evaluating food sources of SFAs suggest neutral or beneficial effects of dairy foods on CVD, whereas intake of meat, and particularly processed meats, has been associated with neutral or increased risk of CVD, associations that may be independent of the SFA content of the foods. On the other hand, vegetarian dietary patterns have generally been associated with reduced CVD risk. It has been suggested that this is related to higher intake of PUFAs, fiber, and micronutrients as well as reduced GL (75), although other unknown or unmeasured lifestyle and dietary variables may be responsible. Both epidemiological and clinical trial data support the cardiovascular benefits of dietary patterns such as the Mediterranean and DASH diets that include vegetables, fruits, nuts, fish, and poultry and minimize sweets and red meats; however, the role of SFAs in such multifactorial diet patterns is unclear."

5) Saturated Fat as Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study (Lanping, L., et al, 2015)

  • "We followed 84,628 women (Nurses’ Health Study, 1980 to 2010), and 42,908 men (Health Professionals Follow-up Study, 1986 to 2010) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by semiquantitative food frequency questionnaire every 4 years."
  • "In our study, replacing saturated fats with monounsaturated fats was associated with a lower CHD risk, suggesting that there are healthful benefits to replacing food sources of saturated fats with plant sources of monounsaturated fats, such as vegetables oils (e.g., olive oil and canola oil), nuts, and seeds. The apparent benefit that we observed for monounsaturated fats is consistent with their effects on LDL and HDL, which are similar to those for polyunsaturated fats."

6) Saturated fat, carbohydrate, and cardiovascular disease (Siri-Tarino, P.W., et al, 2010)

  • "A meta-analysis including 16 prospective observational cohort studies (20–35) that assessed the relation between dietary saturated fat and CHD appears in this issue of the Journal (36). Although some studies reported significant associations either in the entire cohort (28) or in subgroups (21, 22, 35), the overall risk ratio for CHD, after adjustment for relevant covariates, was not significantly increased (risk ratio = 1.07)."
  • "Genetic factors may also contribute to variability in the dietary response to saturated fat (96–98). Among these, the apoE4 isoform, which is associated with increased plasma LDL cholesterol in comparison with the more common apoE3 isoform, has been most consistently found to be predictive of a greater LDL-cholesterol reduction in response to diet (99, 100)."


But we do see that the different types of saturated fats cause different effects and response is magnified in E4s.

Saturated Fatty Acids and Risk of Coronary Heart Disease: Modulation by Replacement Nutrients (Siri-Tarino, P.W., et al, 2010)

  • "Different saturated fatty acids have varying effects on LDL cholesterol, HDL cholesterol, and the TC:HDL cholesterol ratio when they replace carbohydrate [10]. The longer chain stearic acid (18:0) has been shown to have no effect on LDL or HDL cholesterol or the TC:HDL cholesterol ratio, and saturated fatty acids of shorter length have been shown to have a greater LDL cholesterol–raising effect, such that lauric acid (12:0) raised LDL cholesterol the most, followed by myristic (14:0) and palmitic (16:0) acids. Lauric acid also increased HDL cholesterol most significantly, and it did this disproportionately to TC, so that its replacement of carbohydrate actually led to a significant decrease in the TC:HDL cholesterol ratio [10]."
  • "There exists considerable inter-individual variation in the response to dietary saturated fat. The ability of saturated fats to raise LDL cholesterol is enhanced by increased intake of dietary cholesterol as well as baseline LDL cholesterol concentrations [2]. Intrinsic differences in the regulation of lipid metabolism may partly explain the heterogeneity of responses to dietary saturated fat. In fact, an association of the apoE4 allele with a greater LDL response to saturated fat has been reported in a number of studies, although this effect is confounded by the relationship of apoE4 to baseline LDL levels."


But perhaps the negative effects of saturated fat lie in it's relationship to inflammation.

Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. (Kennedy, A., et al, 2009)

  • "Collectively, these studies demonstrate the adverse effects of elevated FFA, especially SFA, on WAT function. Specifically, excess consumption of SFA enhances WAT expansion and adipocyte hypertrophy and subsequent death. These events increase inflammatory signaling and recruitment and activation of macrophages, neutrophils, and BMDC, leading to inflammation, impaired insulin signaling, and insulin resistance in multiple tissues, especially in WAT and muscle."


So even if the cardiovascular risk is not totally clear, there are studies suggesting negative cognitive effects are possible. Whether these effects are wholly due to saturated fats, or other confounding factors such poor dietary and lifestyle choices, is not clear.

Saturated and trans fats and dementia: a systematic review (Barnard, N., et al, 2014)

  • "The Washington Heights–Inwood Columbia Aging Project (WHICAP) included 980 New Yorkers aged ≥65 years, of whom 28% carried the APOE ε4 allele (Luchsinger et al., 2002). After 4 years of follow-up, 242 cases of AD were identified. Alzheimer's risk was positively, but nonsignificantly, associated with saturated fat intake. A subanalysis based on genetic type showed the relationships between energy intake or total fat intake and Alzheimer's risk were primarily found in those with the APOE ε4 allele. This subanalysis was not done for saturated fat intake."
  • "The Chicago Health and Aging Project (CHAP) reported on a stratified sample of 815 individuals in Chicago, IL, aged 65–94 years (mean 73.1 years), of whom 35% carried the APOE ε4 allele (Morris et al., 2003). After 3.9 years of observation, 131 Alzheimer's cases were identified. Intake levels of both saturated and trans fat were positively and significantly associated with Alzheimer's risk."
  • "The Cardiovascular risk factors, Aging and Dementia (CAIDE) study included 1449 individuals in Finland with a mean baseline age of 50.4 years, of whom 35% carried the APOE ε4 allele (Laitinen et al., 2006). After a follow-up of 21 years, 117 cases of dementia were identified, including 76 with AD. Moderate saturated fat intake was positively and significantly associated with both total dementia and AD, but the association did not reach statistical significance for the highest saturated fat intake group. In a subanalysis based on APOE status, elevated risk of AD or dementia related to saturated fat intake appears to have been mainly evident in APOE ε4 carriers; among carriers with moderate (second quartile) saturated fat intake, the odds ratio for incident dementia was 3.16 (95% confidence interval [CI], 1.12–8.91)."


To understand more about the complexities of saturated fats and the impact of diet, you can read through this discussion SFA vs. Dietary Cholesterol restriction.

And check out the thread on Dr. Stavia's experiment with a high saturated fat diet.

Also check out Chris Masterjohn's saturated fat post at Weston Price. His view is, "Saturated fats play essential structural roles in the body, and specific saturated fatty acids have specific benefits to energy metabolism, immunity, intestinal health and metabolic health. There is insufficient evidence to claim that we require some specific amount of saturated fat in our diets every day, so it makes little sense to make dietary decisions based on the fear that we are not getting enough saturated fat. Conversely, because saturated fats play so many beneficial roles, and because our bodies will contain large amounts of saturated fat whether we embrace it in our diets or choose to avoid it, it makes little sense to make dietary decisions based on the fear that we are eating too much saturated fat. Instead, we should dispense with these fears altogether and look toward the menu of traditional fats, seeing a wide array of tools before us to meet our individual needs and priorities. Toward the top of that list for each of us should be preparing wholesome meals that we truly enjoy."


Thyroid problems

1) Thyroid Disease and the Heart (Irwin Klein, Sara Danzi, 2007)

  • "Overt hypothyroidism is characterized by hypercholesterolemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B. Whereas the prevalence of overt hypothyroidism in patients with hypercholesterolemia is estimated to be 1.3% to 2.8%, 90% of patients with hypothyroidism had hypercholesterolemia."

2) Thyroid hormones and cardiovascular disease (Jabbar, A., et al, 2016)

  • "The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations — such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome — adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events."

3) Hypothyroidism and Atherosclerosis (Cappola, A., et al, 2003)

  • "Studies have also shown that hypothyroidism causes qualitative changes in circulating lipoproteins that increase their atherogenicity. Two studies have shown that LDL is more susceptible to oxidation in patients with hypothyroidism, with normalization after restoration of the euthyroid state (22, 23). Increased levels of lipoprotein(a) [Lp(a)], a particularly atherogenic LDL variant in which apolipoprotein(a) and apo B are covalently bound, have also been reported in hypothyroidism, compared with euthyroid controls."


Statins

1) American College of Cardiology Guidelines

Here are the current US guidelines on statins. In 2014, the American College of Cardiology and the American Heart Association released an updated guideline for the use of statins to prevent and treat atherosclerotic cardiovascular disease (ASCVD). There first guideline emphasizes that lifestyle modification remains a critical component of ASCVD reduction.

The ACC found that there was no good evidence to support the current target levels for LDL cholesterol, so they recommended an approach that disregards target levels and is based only on risk level and intensity of statin therapy. If your doctor wants to treat to a target level and your risk is low, you should respectfully ask why.

The guidelines identified 4 groups of individuals for which an extensive body of RCT evidence demonstrated a reduction in ASCVD events with a good margin of safety from moderate- or high-intensity statin therapy:

  • Individuals with clinical ASCVD
  • Individuals with primary elevations of LDL–C ≥190 mg/dL.
  • Individuals 40 to 75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD
  • Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher.

The guidelines are the same for women as for men. They found no evidence to support adjusting treatment to achieve specific target levels of LDL-C.

To understand your individual risk, try the Framingham Cardiovascular 10-Year Risk test.

The Mayo Clinic risk calculator also looks at family history, race and more.

in 2016, the ACC wrote that prescribing for the low risk patient is tricky and stated, "Despite the clinical utility of risk equations, the absolute individual risk of a patient may be difficult to determine by risk equation alone." You can also get a heart scan, also known as a coronary calcium scan, which is a specialized X-ray test that measures calcium-containing plaque in the arteries. Several members of the ApoE4 forums have taken this test, so you can search the archives or post questions if you want to know more.

2) Certain genes and statins don't always play nice

The easiest way to check for genes that don't play nice with statins is download your raw data from 23andme to Promethease and click the Medicine section tab.

In 23andme, you can use the drop-down bar to click Browse Raw Data and type in some common SNPs of statin's responsiveness including rs1723850 (T;T is risk) and rs17244841 (A;A is risk). Unlike the myopathy risk gene, rs4693596 (C;C is risk) found in only 14% of people, the responsive SNPs are found in over 70% of people. Statins might be risker if you're unresponsive, require higher doses and have the muscle damage risk. Our Dr. Stavia notes, even with the doubled risks of this SNP, true muscle damage is rare.

Here's a thread on the cardiac risk genes:https://www.apoe4.info/forums/viewtopic.php?f=5&t=1776&p=20021#p20021

3) FYI: Red yeast rice IS a statin

The molecule made by the plant is the same as the drug lovastatin.


Genetics

MTHFR

1) A plasma proteomics method reveals links between ischemic stroke and MTHFR C677T genotype (Zhang, Z., et al, 2017)

  • "The C677T polymorphism in the gene MTHFR is often associated with cardiovascular diseases (CVD) because it can directly affect folic acid metabolism and also enhance the level of plasma homocysteine, which are considered independent risk factors for ischemic stroke, thrombosis, CVD, and venous thrombosis7. In this study, we identified different types of proteins that are expressed in the plasma of stroke patients with the C677T polymorphism...The differentially expressed proteins mentioned above were mainly involved in the immuno-inflammatory response and the complement cascade."

2) Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes. (Amaral F., et al, 2017)

  • "Significant interactions were observed among the MTHFR C677T, MTHFR A1298C and CBS haplotype 844ins68/T833C polymorphisms in the results for Hcy levels (P = 0.000), where heterozygous had higher values. Interactions among these polymorphisms can affect serum Hcy levels, where multiple heterozygosis could be a risk factor for vaso-occlusive episodes."

3) Riboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension. (McNulty, H., et al, 2017)

  • "Randomized trials conducted in hypertensive patients (with and without overt CVD) pre-screened for this polymorphism show that targeted riboflavin supplementation in homozygous individuals (MTHFR 677TT genotype) lowers systolic blood pressure by 6 to 13 mmHg, independently of the effect of antihypertensive drugs. The latest evidence, that the blood pressure phenotype associated with this polymorphism is modifiable by riboflavin, has important clinical and public health implications. For hypertensive patients, riboflavin supplementation can offer a non-drug treatment to effectively lower blood pressure in those identified with the MTHFR 677TT genotype."

4) C667T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene and susceptibility to myocardial infarction: A systematic review and meta-analysis. (Alizadeh S., et al, 2016)

  • "Unlike A1298C polymorphism, C677T polymorphism was associated with risk of MI in African, North American, and elderly populations."

And many more. Just plug "MTHFR cardiovascular disease" into the PubMed search.