Note from Dave– For the record, Siobhan reads many more studies than I do — and probably you too. This is why I call her our Senior Researcher here at CC. So I asked if she had to narrow down a “Top 10” list for our readers, and as always, she did not disappoint. Enjoy!

10. Total Cholesterol Inversely Associated with ACM In Women

Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study.

doi:10.1111/j.1365-2753.2011.01767.x.

The Reason: The study looked at death rates from all causes (All-Cause Mortality; ACM) in relation to total cholesterol levels, and even went so far as to stratify by gender. For women, the higher the total cholesterol the lower the All-Cause Mortality, and Cardiovascular Disease Mortality. For men, it was a “U” shaped curve (higher mortality at both higher and lower ends of total cholesterol). This highlights how potentially complicated cholesterol is as a risk factor and the potential hazards of applying results from one group (men) to the entire population which may result in potentially damaging outcomes.

“If our findings are generalizable, clinical and public health recommendations regarding the ‘dangers’ of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.”

9. Lipoprotein(a) Structure and Function Review

Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies

doi:10.1007/s11789-017-0084-1

The Reason: While there are still many things to learn about Lipoprotein(a), a review paper covering what we do know so far can clear up many misunderstandings before they appear. This paper also covers a little bit of Lp(a)’s wound healing and tissue repair functions, as well as general structure.

“Earlier works agree that Lp(a) accelerates wound healing and tissue repair, and therefore Lp(a) provided an evolutionary advantage to humans […]”

8. Undiagnosed Diabetes in People with Heart Disease

Screening for dysglycaemia in patients with coronary artery disease as reflected by fasting glucose, oral glucose tolerance test, and HbA1c

doi:10.1093/eurheartj/ehv008

The Reason: While not strictly related to the lipid system, heart disease is a topic that comes up frequently when studying lipoproteins. This study helps provide more context to what is going on “under the hood” in those with heart disease – as it demonstrates that when testing for signs of diabetes in those with heart disease, a full ¾ of them who had been considered “non-diabetic” previously either were diabetic, or were at high risk of developing diabetes. Take note that the testing they had done didn’t include insulin, so whether the remaining quarter of people were truly nondiabetic remains unknown.

“In addition, the total proportion of patients identified with diabetes and other forms of dysglycemia varied from 90% using the ADA criteria for FPG + HbA1c to 73% using the WHO criteria for OGTT = FPG + 2hPG.”

7. Lipoproteins as Part of the Immune System

Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.

doi:10.1194/jlr.R300019-JLR200

The Reason: This review covers a topic that I rarely ever see addressed – the involvement of lipoproteins in the immune system. Not only do lipoproteins bind to pathogens to help with their disposal, and help with repair after injury, but they are also upregulated during inflammation and infection. These lipid profiles can be an important symptom of underlying issues that provide a window into how the system is doing overall, and for understanding how the processes of defense and repair work.

“The [Acute Phase Response] induced during infection/inflammation protects the host from further injury […]”

6. Macrophages’ Role in Atherosclerosis

Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

doi:10.1155/2016/9582430

The Reason: Although lesser known than some other components to the disease, macrophages play multiple roles in the development of atherosclerosis, even beyond being necessary for the formation of lipid laden foam cells. Some of these include initiating and sustaining the inflammatory response, and aiding in repair. Even foam cell formation is more complex than it appears at first glance, and this paper covers the complexities quite well.

“LDL serves as the primary source of lipid accumulation in the arterial wall during atherosclerotic lesion development. In vitro studies have demonstrated that intracellular cholesterol accumulation is caused not by native but by atherogenic modified LDL.”

5. Impact of Inflammation on HDL Levels and Function

Effect of inflammation on HDL structure and function

doi:10.1097/MOL.0000000000000333

The Reason: A more in-depth look at what impact inflammation has on HDL levels, structure, and function. This information is not only important for understanding the lipid system as a whole, but also to grasp what may cause lower HDL levels, and why structure (and function) matters even beyond levels in themselves, but also why the levels are important and what they represent about how the system is functioning as a whole.

“We would propose that these changes are advantageous during infections and following acute injuries. For example, decreasing reverse cholesterol transport or increasing LDL oxidation would increase cholesterol levels in macrophages where it could stimulate host defense and repair.“

4. High HDL, Low TG Yield Better Risk Odds Regardless of LDL Level

Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?

doi:10.1161/CIRCOUTCOMES.115.002436

The Reason: This analysis uses data from the Framingham Offspring Study, but puts a new spin on it to separate out people with high or low HDL levels, high or low triglyceride levels, and high or low LDL levels (with varying cutoffs for LDL and triglycerides). The results were that irrespective of LDL levels (ranging from <100, >100, >130) risk for heart disease was nearly the same so long as you had high HDL and low triglycerides. This makes sense as low triglycerides and high HDL is typically associated with better metabolic health, and although the data is not definitive by any means it does raise some interesting questions about whether the same holds true for people with very high HDL, very low triglycerides, and LDL far above the cutoff point they listed (AKA Lean Mass Hyper Responders).

“[…] high HDL-C […] was consistently associated with reduced CVD risk[.] This association persisted even when high HDL-C was accompanied by higher LDL-C (≥100 and ≥130 mg/dL) or higher TG (≥100 and ≥150 mg/dL), but was no longer significantly [sic] protective when both LDL-C and TG equaled or exceeded 100 mg/dL.”

3. Overview of Cholesterol Levels and Risk of Disease, All-Cause Mortality

Towards a Paradigm Shift in Cholesterol Treatment. A Re-examination of the Cholesterol Issue in Japan.

DOI:10.1159/000381654

The Reason: Typically, when hearing about cholesterol levels in the mainstream (and sometimes even in smaller niches) it is often referred to as bad, and the higher it is, the worse it is. However, this study provides a bit of a different perspective, with higher total cholesterol being related to lower incidence of certain diseases, infectious death, and lower all-cause mortality. The correlations are particularly interesting when combined with the thought of serum cholesterol often being portrayed as a dose-dependent poison, when reality may be a fair bit more complicated than that.

“[…] all-cause mortality was essentially inversely correlated with LDL cholesterol levels in both men and women.“

2. Cholesterol Accumulation Is Not the Initiating Factor to Atherosclerosis – Arterial Thickening Is

Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis.

doi:10.1186/1742-4682-9-11

The Reason: Although cholesterol accumulation via foam cell formation does occur later down the line in atherosclerosis, there appear to be many steps that occur before that happens. Namely, arterial thickening to the point of neovascularization (the artery becoming thick enough to require additional blood supply; thickening occurring from mechanical stress or damage) being a key initiating factor. While lipid deposition is still involved in the process once neovascularization occurs (via vascular remodeling and proteoglycans), the key point is that lipid deposition is not the initiating factor for the disease, but rather may actually be arterial damage and remodeling.

“This neovascularization, originating from adventitial vasa vasorum, is observed prior to the appearance of any atherosclerotic features except an increased dimension of DIT.”

1. Insulin, Insulin Resistance Differentiating Factor for MI Occurrence in Those with FH

Fibrinolytic parameters and insulin resistance in young survivors of myocardial infarction with heterozygous familial hypercholesterolemia.

The Reason: The study took two groups of people with Familial Hypercholesterolemia (FH; an umbrella of genetic causes for high cholesterol levels) and separated them based on whether they had experienced a myocardial infarction (MI) or whether they hadn’t. Interesting, the differentiating factor between the two groups wasn’t LDL, as you might expect, but rather other factors like triglyceride level, insulin level, and level of insulin resistance, among others. This may provide information to point in a direction for investigation for people with non-genetically high LDL but otherwise low markers for insulin resistance.

“There was no difference in total and LDL cholesterol between the two groups. Patients with previous myocardial infarction had significantly higher levels of insulin, insulin resistance, triglycerides, t-PA antigen, PAI-1 antigen and activity, and significantly lower values of HDL cholesterol.”