GRID VIEW
I’ve been watching horror films lately, so before we get into the main topic of lipoproteins let’s talk about blood. Blood is watery and kind of gross but very useful. I like to think of the bloodstream as a highway we use to transport nutrients, cells, molecules, water, and waste to and from all the cells in the body. One problem with blood is that it can’t transport things that don’t dissolve in it very well. Fats, also called lipids, don’t dissolve in water, a lesson I think we all learned with the old oil and water demonstration from elementary school. Because of this, the body bundles lipids into little packages that can dissolve in watery blood. These packages combine water-repelling lipids with special proteins that organize them so they can flow through the blood. These lipid-protein packages are called lipoproteins. They have more functions than just transport, but that’s the one we’re focusing on today.
Lipoproteins are very neat. The outside is a membrane very similar to a human cell. The inside is a mix of lipids, including triglycerides and cholesterol, and the proteins hold everything together. Lipoproteins travel through the bloodstream, carrying important lipids to cells all over the body. They can be sorted by size and “density,” but density is defined differently here, more like buoyancy. Imagine a pot of water. Olive oil is almost entirely made of lipids, and if you pour it into the pot of water it floats on the surface; it’s low-density. A steak contains a lot of fatty lipids, but there’s also a ton of protein in steak. Toss it in a pot of water and it sinks (and becomes gross); it’s high-density. Lipoprotein density is more about the ratio of lipid to protein. Even more fascinating is that the ratio of lipid to protein can change over time! A very low-density lipoprotein (VLDL) will deliver triglycerides (a type of lipid) from the liver to cells, lose some density, and may become an intermediate-density lipoprotein (IDL). These are proportionally higher in cholesterol. An IDL may deliver more lipids to become a low-density lipoprotein (LDL). LDL is the primary transporter of cholesterol through the body and delivers it to cells, which use cholesterol for some essential purposes, including maintaining the membrane that surrounds cells. High-density lipoproteins (HDL) work in reverse. They transport cholesterol from the cells back to the liver, getting larger (and lower in density) as they pick up more material.
Lipoproteins aren’t just determined by their size, however. Connected to the lipoproteins are other special proteins called apolipoproteins (apo– meaning “next to” or “away”). These determine how lipoproteins form, act, are recognized, and are broken down. One dangerous lipoprotein variant is apolipoprotein (a), usually shortened to apo(a). When this attaches to an LDL-like particle, it is called Lp(a). Since the names are important and the letter “a” is common in this space, it is usually pronounced “Lp little a.” Lp(a) is bad news.
When apo(a) attaches to an LDL, everything changes. The density of Lp(a) changes and it is more likely to clog the bloodstream. High amounts of low-density lipoproteins (including Lp(a)) can cause a lot of damage to the cardiovascular system, increasing the chances of serious cardiovascular events like cardiovascular disease, heart attack, and stroke. Even worse, the body can’t break down Lp(a) the same way it does LDL, so the problems of high “bad” cholesterol are compounded. Because of this, classic methods of controlling cholesterol – lifestyle changes like diet and exercise, statins, and other medication typically have no effect on Lp(a) levels!
High Lp(a) is a serious health problem, affecting around 20% of people. Levels of Lp(a) in the bloodstream can vary up to 1000x from person to person! The highest levels are seen in Black and South Asian populations. As stated earlier, Lp(a) levels are unaffected by normal risk factors. Instead, Lp(a) is genetically controlled. If your parents have elevated Lp(a), it is likely you will too. The problem is one of several genetic mutations that affect the amount of Lp(a) created. As we discovered earlier, Lp(a) doesn’t break down like normal LDL, so levels are primarily determined by how much is produced.
So what can we do if we have high Lp(a)? As unintuitive as it sounds, diet and exercise are still good options! This isn’t because they affect Lp(a) levels, but because a healthy lifestyle can help protect your heart. Medications that protect the cardiovascular system may also be protective against high Lp(a) levels. Currently, in extreme cases, some patients may undergo a process called lipoprotein apheresis. This is where the blood is removed from the body and lipoproteins are physically separated from the blood before it is returned to the body, just like a good horror movie! Clinical trials are investigating methods of enhancing the body’s ability to break down Lp(a) or disrupt the production of Lp(a). Production may be targeted by disrupting the body’s ability to produce apo(a)! Consider joining a research study to help find new treatment options for high Lp(a). Also, with Lp(a) day approaching on March 24th, impress all your friends with your new pedantic vocabulary.
Staff Writer / Editor Benton Lowey-Ball, BS, BFA
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References:
Biggerstaff, K. D., & Wooten, J. S. (2004). Understanding lipoproteins as transporters of cholesterol and other lipids. Advances in physiology education, 28(3), 105-106. https://journals.physiology.org/doi/full/10.1152/advan.00048.2003
Devaraj, S., Semaan, J. R., & Jialal, I. (2019). Biochemistry, apolipoprotein B. https://europepmc.org/article/NBK/nbk538139
Feingold, K. R. (2024). Introduction to lipids and lipoproteins. Endotext [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK305896/
Kamstrup, P. R., Neely, R. D. G., Nissen, S., Landmesser, U., Haghikia, A., Costa-Scharplatz, M., … & Nordestgaard, B. G. (2024). Lipoprotein (a) and cardiovascular disease: sifting the evidence to guide future research. European Journal of Preventive Cardiology, zwae032. https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwae032/7585314
Koschinsky, M. L., Stroes, E. S., & Kronenberg, F. (2023). Daring to dream: Targeting lipoprotein (a) as a causal and risk-enhancing factor. Pharmacological Research, 106843. https://www.sciencedirect.com/science/article/pii/S1043661823001998
Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., … & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. https://www.mdpi.com/1420-3049/28/3/969
Schmidt, K., Noureen, A., Kronenberg, F., & Utermann, G. (2016). Structure, function, and genetics of lipoprotein (a). Journal of lipid research, 57(8), 1339-1359. https://www.jlr.org/article/S0022-2275(20)35208-1/fulltext
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Fats are necessary for survival. In the body, we call them lipids. They are needed to build the borders of our cells, create molecules and hormones, coat important neurons in the brain, protect and insulate our organs, store energy between meals, and perform many other vital functions. Lipids are fats, which don’t play well with water; think Spongebob and Squidward (or oil and water). Lipids need to be transported through the bloodstream by proteins. Lipids attach to these proteins to make lipoproteins (lipid + protein). Triglycerides are the most common type of lipid found in the body. They are used as energy for muscles and are stored in fat cells. They are transported in very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and gut-produced chylomicrons. Cholesterols are needed for parts of our cells and are some of the building blocks of hormones, bile acids, and enzymes. Important types of cholesterol lipoproteins include low-density lipoproteins (LDL), high-density lipoproteins (HDL), and Lipoprotein(a) (Lp(a)). Our body stays healthy in part by maintaining a healthy balance of these lipids and lipoproteins.
Keeping the balance of lipids is critical to our health. When it is out of whack, we experience dyslipidemia. Dys– meaning “bad,” lipid- indicating the lipids, or fats, and -emia meaning “presence in blood”. Dyslipidemia, or bad lipid presence in blood, is when the lipids in the blood are out of balance. This condition is unsettlingly common — one of every three American adults 20 years or older has dyslipidemia. Any imbalance falls under this description, but the most common and dangerous types in the USA are high LDL cholesterol, low HDL cholesterol, and high triglycerides. The prefix hyper- means “high,” so high cholesterol is called hypercholesterolemia (high cholesterol presence in blood); high triglycerides are hypertriglyceridemia (high triglyceride presence in blood); and a combination of both is simply called combined dyslipidemia. Some people suffer from hypolipidemia (low lipid presence in the blood), but it is much rarer in the USA.
Because dyslipidemia is defined and diagnosed with a blood test, the underlying causes can vary, unlike conditions such as sickle cell anemia or chicken pox. Primary causes are genetic, where you inherit a risk factor. This might look like elevated Lp(a) levels, which are heavily influenced by genetics. Secondary causes are anything that may alter lipid levels, including diabetes, obesity, an unhealthy diet high in triglycerides, and lack of exercise. Regardless of the cause, the effects can be deadly. The biggest, most obvious problem is atherosclerotic cardiovascular disease (ASCVD), when cholesterols, fats, and other materials build up on the inside of our blood vessels. These buildups, called plaques, can block blood flow to the heart, brain, or other parts of the body, potentially causing heart attack, stroke, and/or pain in the body and limbs.
With these outcomes in mind, solutions are critical. As with almost every non-infectious disease, some of the best methods for preventing complications are a healthy lifestyle. A diet high in vegetables, fruits, and whole grains may help. Keeping calorie counts low and moderate-to-vigorous exercise is also recommended, if possible. Beyond lifestyle, medications have helped many people. Statins like Lipitor are typically the first line of defense. They are the most widely prescribed class of drugs in the world, though not everyone can tolerate them. They inhibit an enzyme called HMG-CoA reductase. Statins can lower LDL levels by slowing the cholesterol-making process. PCSK9 is another important enzyme in the creation of cholesterol. PCSK9 inhibitors target this enzyme to help reduce cholesterol if statins aren’t working. Bempedoic acid and icosapent ethyl may also help reduce the amount of cholesterol the liver makes. Ezetimibe (uh·zeh·tuh·mibe) reduces the amount of cholesterol absorbed. Beyond lowering lipid levels, other medications may help reduce the risk of cardiovascular disease. Finally, if medications aren’t tolerated or effective enough, blood plasma can be removed, cleaned outside the body, and pumped back in using a process called plasmapheresis.
Fats may be necessary for survival, but too many in the bloodstream can be deadly.
Staff Writer / Editor Benton Lowey-Ball, BS, BFA
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References:
Berberich, A. J., & Hegele, R. A. (2022). A modern approach to dyslipidemia. Endocrine Reviews, 43(4), 611-653. https://academic.oup.com/edrv/article/43/4/611/6408399?login=true
Feingold, K. R. (2015). Introduction to lipids and lipoproteins. https://www.ncbi.nlm.nih.gov/books/NBK305896/
Pappan, N., & Rehman, A. (2023). Dyslipidemia. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK560891/
Pokhrel, B., Yuet, W. C., & Levine, S. N. (2017). PCSK9 inhibitors.https://www.ncbi.nlm.nih.gov/books/NBK448100/
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Cardiovascular disease has remained the number one cause of death worldwide. Multiple clinical trials have revealed that a common and modifiable risk factor for cardiovascular disease is high cholesterol, and if a person lowers their cholesterol, they can lower their risk for heart-related diseases.
Most of us have heard of cholesterol, but what is it? Why is having too much cholesterol a bad thing? How do we get cholesterol in our bodies? What can you do to lower your cholesterol to healthy levels?
Cholesterols are a broad and useful type of fat found in the body. The body needs them to create hormones, essential vitamins (like vitamin D), and other molecules. They float on the surface of our cells, helping to maintain the structure and function of cell barriers. Cholesterols regulate cell activity and act outside of cells. They insulate the neurons in our brain, allowing us to think. In fact, cholesterol is so important to daily function, that every cell in the body can make cholesterol from basic materials, except your eyelashes!
There are times when cholesterol is downright bad. LDL cholesterol and Lipoprotein a [Lp(a)] have some particularly sticky portions that can get stuck to the inside of our bloodstream. We call one of these portions ApoB. Sticky cholesterol obstructs blood flow in the form of plaques. Without help, this leads to atherosclerosis, scarring, and hardening of the arteries. Atherosclerosis further cascades into cardiovascular disease, clots, heart attacks, and stroke. This is very bad. Unfortunately, it is also very common; atherosclerosis in the neck is found in ¼ of people worldwide. Lowering excess cholesterol is a global health concern.
Our liver creates enough cholesterol to supply our bodies. We are also able to absorb cholesterol from our diets and make some in other cells. The most effective methods of reducing cholesterol are lifestyle and diet changes. However, for some people, diet and exercise don’t seem to budge their cholesterol numbers at all. For others, the ability to exercise and dietary restrictions may be limited. This is where medications can step in.
To understand how a medication may reduce LDL and/or Lp(a), we need to learn a bit about how the body makes things from DNA. Genes are bits of DNA that contain the blueprint for a protein. Genes provide the blueprint to messenger RNA (mRNA). The mRNA translates genetic code into proteins. The cells then fold proteins into complicated, machine-like shapes. Proteins interact with molecules and other proteins to create all sorts of things for the body – including cholesterol. Clinical research has been expanding which of these steps we can target for medications.
Statins are the first line treatment for reducing cholesterol. They target hydroxymethylglutaryl coenzyme A (HMG-CoA). HMG-CoA is a protein used to construct cholesterol molecules. Reducing HMG-CoA slows the body’s ability to create cholesterol, lowering cholesterol levels. Statins block the production of the “bad” LDL-C cholesterol and lower levels by as much as 60%. The benefits for statins to reduce cardiovascular events have been proven in multiple clinical trials over a diverse patient population.
Other oral medications, including ezetimibe and bempedoic acid, can be taken with statins. Ezetimibe can lower LDL-C levels by approximately 20% by inhibiting cholesterol absorption in the intestines, making it a useful add-on medication when statins alone are insufficient. Bempedoic acid can lower LDL-C by 15-25% by decreasing cholesterol synthesis in the liver. Because bempedoic acid is converted to an enzyme found only in the liver and not the muscles (like statins), it is often an alternative for patients who have statin-associated muscle myalgias.
Monoclonal antibodies (MoAbs) are a newer class of medication. MoAbs like alirocumab and evolocumab act like signaling molecules. These two stay outside of cells and tell the liver to produce less of the protein PCSK9. Controlling PCSK9 is a newer method of changing a person’s cholesterol profile. PCSK9 controls how much extra LDL cholesterol is absorbed and recycled by cells. MoAb medications affect this by targeting signaling receptors on the outside of the liver.
Even newer medications target the process by which genes get turned on inside the cells. They are called gene silencing therapies because they aim to “silence” the gene’s effects. Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) stop the liver from producing functional LDL or Lp(a) mRNA molecules. These act at different, very early stages of the cholesterol process. In addition, specialized packaging on the medications deliver them to the liver and not other cells. This can make for very targeted medications that (hopefully) have fewer side effects.
Inclisiran is the first FDA-approved siRNA therapy to lower LDL cholesterol. It is a subcutaneous injection taken twice a year. Imagine going to your physician’s office just twice a year to get your “cholesterol vaccine”!
Even more amazing, gene editing tools such as CRISPR could reduce overexpression of PCSK9 or other genes on a long-term basis. These are still in early phase trials, but the future is looking bright.
Lipoprotein a,or “L-P-little-a”, or Lp(a), is a new target for decreasing the risk of cardiovascular disease. Lp(a) is genetically inherited and increases the risk for both heart disease and stroke because it can promote plaque buildup, blood clots, and inflammation. New gene silencing therapies are in clinical trials right now using both ASO and siRNA technology.
Diet, lifestyle changes, and statins remain the front-line defense against high cholesterol. New medicines may work with or replace these classical defenses. As technologies move through the clinical research apparatus, we may be able to tailor custom combinations of medications for individual patients. ENCORE Research Group has been involved in every step along this path, helping to study medications in every category. Join our team and help pave the way for new medications to help combat high cholesterol!
Sources:
Craig, M., Yarrarapu, S. N. S., & Dimri, M. (2018). Biochemistry, cholesterol. https://www.ncbi.nlm.nih.gov/books/NBK513326/
Fernandez-Prado, R., Perez-Gomez, M. V., & Ortiz, A. (2020). Pelacarsen for lowering lipoprotein (a): implications for patients with chronic kidney disease. Clinical Kidney Journal, 13(5), 753-757. https://doi.org/10.1093%2Fckj%2Fsfaa001
Prati, P., Vanuzzo, D., Casaroli, M., Di Chiara, A., De Biasi, F., Feruglio, G. A., & Touboul, P. J. (1992). Prevalence and determinants of carotid atherosclerosis in a general population. Stroke, 23(12), 1705-1711. https://doi.org/10.1161/01.str.23.12.1705
Tokgözoğlu, L., & Libby, P. (2022). The dawn of a new era of targeted lipid-lowering therapies. European Heart Journal. https://doi.org/10.1093/eurheartj/ehab841
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If someone in your family had a heart attack or stroke before the age of 60, you could be at risk and might want to have your blood tested for this little-known hereditary risk factor, Lp(a). Cardiovascular disease remains the leading cause of death in the United States, even during the COVID-19 pandemic. Determining and reducing the risk factors for cardiovascular disease is critical.
Lipoprotein(a), also called Lp(a), pronounced “LP Little a” is a particularly dangerous culprit. Its levels are controlled by a single gene, and a single genetic variation in this gene is enough to drastically change Lp(a) levels. Unfortunately, since it is genetically determined, diet, exercise, and lifestyle have little or no effect on Lp(a) levels. High Lp(a) can contribute to several cardiovascular conditions. These include a two to three times increase in the risk of developing:
- Coronary heart disease
- Peripheral heart disease
- Aortic valve stenosis
- Ischemic stroke
Lp(a) has been referred to as the evil twin of the more familiar LDL (bad) cholesterol and is a triple threat because it is:
- Pro-atherogenic: higher risk fatty deposits in the walls of arteries
- Pro-thrombotic: promotes blood clots
- Pro-inflammatory: inflammation is an important risk of cardiovascular disease
There are two methods of measuring Lp(a). The most common method of measuring Lp(a) is by mass, in mg/dL. Measuring how many individual particles, regardless of size, is another method and is measured in nmol/L. It is important to know which method was used when understanding your numbers. If you have never had your Lp(a) level checked, we offer Lp(a) testing to our ENCORE community for those who pre-qualify (call for details).
Currently, there are no approved therapies to lower Lp(a) levels and reduce one’s risk. However, three exciting therapies are currently being studied in clinical trials at ENCORE Research Group sites across Florida. The good news is that because of clinical research and your involvement, we have new treatments for elevated Lp(a) on the horizon!
Written by Benton Lowey-Ball, BS Behavioral Neuroscience
Sources:
Kamstrup, P. R. (2021). Lipoprotein (a) and cardiovascular disease. Clinical chemistry, 67(1), 154-166. https://doi.org/10.1093/clinchem/hvaa247
Miksenas, H., Januzzi, J. L., & Natarajan, P. (2021). Lipoprotein (a) and cardiovascular diseases. JAMA, 326(4), 352-353. doi:10.1001/jama.2021.3632
Health.harvard.edu
Amgenscience.com
5 Things to Know about Lp(a)
Lipoprotein(a), or Lp(a), is an independent risk factor for atherosclerotic cardiovascular disease. Cardiovascular disease is the leading cause of death in both men and women in the US and globally . You may have heard of LDL cholesterol, or “bad cholesterol,” as a risk factor for heart disease, but Lp(a) can be just as dangerous. Lp(a) flies under the radar of many physicians. This is because the awareness of Lp(a) is still very low, very little is understood about the protein and the treatment options are limited.
What is LP(a)?
Lp(a), pronounced “LP little a,” is a protein that is attached to LDL cholesterol. It is composed of an LDL-like particle, but it has a second protein coiled around it. Recent studies have shown that people born with elevated Lp(a) can be two to four times as likely to have a heart attack or serious cardiac related risk. Lp(a) is present in 20% of the population.
What differentiates LP(a) from other heart disease risk factors?
LP(a) is so unique because it is a completely genetic risk factor. Meaning, having an elevated LP(a) is almost entirely determined by the genes you inherit. There is no evidence that a healthy lifestyle will lower your Lp(a). However, that does not mean those with high levels shouldn’t practice healthy habits. Reducing other risk factors that are determined by quality of health can still reduce the overall risk of heart disease.
Another risk factor that sets LP(a) apart is that it is an independent risk factor. It has been linked to heart disease in younger adults who are otherwise healthy and have no prior cardiovascular risks. Elevated LP(a) has affected the lives of many who are otherwise healthy. For example, Tennis legend Arthur Ashe, who had his first heart attack at age 36. Bob Harper, a celebrity fitness trainer was also affected and nearly died of a heart attack at age 52.
Who should be tested for Lp(a)?
Studies show that there is a higher risk of a cardiovascular event if Lp(a) levels start to rise above 30 mg/dl. There is an even greater risk at levels 50 mg/dl and higher. There are an estimated one in seven people at or above this threshold. If you’ve had a cardiac event but your cholesterol levels are normal, or you have a family member with heart disease at an early age, have a cardiovascular event despite normal lipid levels, have a family history of Lp(a), or have aortic valvular disease at an early age then you should get tested for Lp(a).
As mentioned, Lp(a) is a genetically mediated risk factor. “This means it runs in families,” Albert Lopez, MD, DO, FASPC, internal physician and lipid specialist in Jacksonville, FL says. “Those individuals that have it, you have a 50% chance of giving to your children.” Dr. Lopez believes there should be cascade screening, meaning asking family members if they have it and then getting tested.
No FDA approved remedies for Lp(a)
Currently there are no FDA approved remedies for elevated Lp(a). Statins, a widely known and used therapy that lowers LDL cholesterol does not reduce Lp(a) and has been shown to sometimes result in a slight increase. One therapy that has been shown to work is asphersis. This process filters a patient’s blood by circulating it through a machine and removing Lp(a) particles. However, this process is reserved for high-risk patients because it is extremely expensive, requires weekly visits and involves risks. After stopping apheresis, the Lp(a) levels begin to rise again.
New Advancements in Science regarding Lp(a)
Luckily, there are new drugs on the horizon that could potentially help those suffering from elevated Lp(a) levels. “What is exciting is that we are in totally nerd, sci-fi treatments now,” Dr. Lopez says. “We can actually stop your genes from making this protein by using a little snip that crinkles it up and doesnt let it read.” In other words, new studies are using gene silencing techniques to achieve a large and durable reduction of Lp(a).
These therapies and medicines are still in clinical trials now. ENCORE Research group is conducting research studies for people with elevated Lp(a) in hopes to find a drug that will lower Lp(a) levels. It is up to the public to participate in these research studies to help those suffering from elevated Lp(a) levels.
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