Atherosclerosis is a condition in which fatty lesions form to narrow and weaken blood vessels. It causes a sizable percentage of all deaths in old age, via stroke or heart attack when lesions rupture. Much of the focus in the medical and research communities is on cholesterol in the bloodstream as a contributing factor to the condition, but atherosclerosis should be thought of as being primarily caused by the dysfunction of the macrophage cells responsible for removing cholesterol from blood vessel tissues, handing it off to HDL particles to return to the liver. In youth these cells function just fine, and young people don't develop lesions. In old age, however, it is a different story.
Macrophages are vulnerable to oxidized cholesterol and to the signaling of chronic inflammation. Both can degrade their ability to transport cholesterol, and they can develop into senescent foam cells that make the local environment even more inflammatory. They also die in large numbers, overwhelmed by cholesterol, and the debris of cell death expands the lesion that the macrophages should be helping to remove. It is because oxidized cholesterol is important in this process that reductions in overall cholesterol in the bloodstream can slow the progression of atherosclerosis. Treatments such as statins have become widely used as a result, but they do not lead to significant reversal of existing lesions.
Scientists here note that most of the work on atherosclerosis to date focuses on reducing LDL cholesterol in the bloodstream, which is to say cholesterol attached to an LDL particle. But other forms of cholesterol are also present in the blood stream, the so-called remnant cholesterol, and the research community has underestimated its presence and contribution to atherosclerosis. This has implications for the various approaches taken to try to control the condition, and further demonstrates that perhaps it is a better idea to focus on the macrophages rather than on the cholesterol. If macrophages can be made resilient to oxidized cholesterol, either by removing that cholesterol in a targeted way, by preventing it from being created in the first place, or by giving the macrophages additional capabilities, as we're working on at Repair Biotechnologies, then this should go a long way towards the goal of reversal of atherosclerosis.
Three quarters of the Danish population have moderately elevated levels of cholesterol. If cholesterol levels are too high, risk of cardiovascular disease is increased. Often, LDL cholesterol, the so-called bad cholesterol, is considered the culprit. However, new research shows that a completely different type of cholesterol may be more responsible than previously assumed. What we are talking about is remnant cholesterol To their surprise, the researchers have discovered that the amount of remnant cholesterol in the blood of adult Danes is much higher than previously believed. From the age of 20 until the age of 60, the amount in the blood is constantly increasing, and for many people it remains at a high level for the rest of their lives.
"Our results show that the amount of remnant cholesterol in the blood of adult Danes is just as high as the amount of the bad LDL cholesterol. We have previously shown that remnant cholesterol is at least as critical as LDL cholesterol in relation to an increased risk of myocardial infarction and stroke, and it is therefore a disturbing development." The results are based on data from people from the Copenhagen General Population Study. A total of 9,000 individuals had cholesterol in their fat particles in the blood measured by metabolomic techniques. "Previous studies from the Copenhagen General Population Study show that overweight and obesity are the main cause of the very high amount of remnant cholesterol in the blood of adult Danes. In addition, diabetes, hereditary genes and lack of exercise play a part."
In 2018, a large international, controlled clinical trial was published that clearly showed that when triglycerides and thus remnant cholesterol were reduced by the help of medication in people with elevated levels in the blood, the risk of cardiovascular disease was reduced by 25%. "Our findings point to the fact that prevention of myocardial infarction and stroke should not just focus on reducing the bad LDL cholesterol, but also on reducing remnant cholesterol and triglycerides. So far, both cardiologists and GPs have focused mostly on reducing LDL cholesterol, but in the future, the focus will also be on reducing triglycerides and remnant cholesterol."
Increased concentrations of calculated remnant cholesterol in triglyceride-rich lipoproteins are observationally and genetically, causally associated with increased risk of ischemic heart disease; however, when measured directly, the fraction of plasma cholesterol present in remnant particles is unclear. We tested the hypothesis that a major fraction of plasma cholesterol is present in remnant lipoproteins in individuals in the general population.
We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined.
Mean nonfasting cholesterol concentration was 72 mg/dL for remnants, 78 mg/dL for LDL, and 71 mg/dL for HDL, equivalent to remnants containing 32% of plasma total cholesterol. Of 14 lipoprotein subclasses, large LDL and IDL were the ones containing most of plasma cholesterol. The plasma concentration of remnant cholesterol was from 54 mg/dL at age 20 to 74 mg/dL at age 60. Corresponding values for LDL cholesterol were from 58 mg/dL to 81 mg/dL. Thus, using direct measurements, one third of total cholesterol in plasma was present in remnant lipoproteins, that is, in the triglyceride-rich lipoproteins IDL and VLDL.