Is the Deadliest Condition Preventable? Understanding ASCVD and LDL-C

Imagine if the deadliest condition was preventable ^[1]. Atherosclerotic Cardiovascular Disease (ASCVD) is the underlying condition that causes heart attack and stroke, which are the first and third most common cause of death worldwide ^{[1, 2, 3]}. The word “atherosclerosis” comes from the Greek words athero- which means “gruel” (referring to the porridge-like plaques found in diseased blood vessels), and -sclerosis meaning “hardening.” Atherosclerotic cardiovascular disease is a hardening of the system that includes the heart (cardio) and blood vessels (vascular) caused by fatty plaques. ASCVD takes a long time to develop, and the effects can last a lifetime. Complications include heart attack, stroke, coronary artery disease, peripheral artery disease, and heart disease.

There are many risk factors associated with ASCVD, including:

• Elevated LDL-cholesterol (LDL-C) levels
• Hypertension
• Diabetes/Insulin resistance
• Smoking
• High triglycerides
• Inflammation
• Sedentary lifestyle
• Obesity

Of these risks, however, high LDL-C has by far the most evidence that it causes ASCVD. A 2017 meta-analysis of two million people enrolled in high-quality studies found compelling evidence of LDL-C’s impact on atherosclerotic cardiovascular disease ^[3]. The evidence is so overwhelming that some researchers claim LDL-C is the “only causal risk factor ^[4].”

What is LDL cholesterol, and how does it cause porridge-like plaques in the cardiovascular system? LDL-C stands for “low-density lipoprotein cholesterol” and is a complex particle made of fatty lipids (lipo-) and proteins that transports lipids around the body. It usually travels in the bloodstream and can enter cells that need extra lipid energy through highly controlled cell receptors. However, when LDL-C levels in the bloodstream are high, the system breaks down. The cells that form the borders of veins and arteries - called epithelial cells - can’t keep the border shut, and LDL-C can enter the space behind them ^[5]. LDL-C then gets trapped and can be oxidized, making them dangerous. Oxidized LDL-C particles release inflammatory signals, which cause an inflammatory immune response. The immune system can’t properly eliminate the LDL-C particles and instead worsen the situation ^[6]. Eventually, a hard plaque of LDL-C, immune cells, muscle cells, and other detritus forms, releasing inflammatory signals and blocking blood flow. In the worst cases, this hard plaque breaks off and blocks blood vessels leading to essential organs like the heart or brain.

How can such devastating consequences be preventable? The best way to treat ASCVD is to prevent it in the first place ^[4]. Non-pharmaceutical preventative methods encourage a healthy lifestyle ^[7]:

• Eat healthy foods: fruits, vegetables, whole grains, nuts
• Avoid eating unhealthy foods: trans fat, red meat, excess sugars, sweetened beverages
• Exercise: 2 ½ hours a week of moderate-intensity exercise, or half as much vigorous activity
• Quit smoking

Clearly, this is much easier said than done, as evidenced by - once again - ASCVD being the leading cause of morbidity and mortality worldwide ^[3]. Standard pharmaceutical treatments target LDL-C in a few clever ways:

• Statins are the standard of care and lower the amount of LDL-C made by the liver
• PCSK9 inhibitors increase the amount of LDL-C taken out of the bloodstream
• Bile acid sequestrants, ezetimibe, and bypass surgery reduce cholesterol absorption
• First in class siRNA therapy, LEQVIO (inclisiran) inhibits the production of PCSK9

Patients with high LDL-C levels should talk with their doctor to find the best treatments to get LDL-C to target levels. Unfortunately, even with the high effectiveness of medication and a high risk of developing ASCVD caused by unmanaged LDL-C, the majority of patients are still receiving inadequate treatment ^[1]. Clinical trials continue to seek new treatments to help lower the risks and complications due to ASCVD. If treatments that improve accessibility, affordability, and adherence are found, we may be able to finally prevent the deadliest condition on earth.

Creative Director Benton Lowey-Ball, BS, BFA

References:

^[1] Makover, M. E., Shapiro, M. D., & Toth, P. P. (2022). There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness. American Journal of Preventive Cardiology, 12, 100371. https://pmc.ncbi.nlm.nih.gov/articles/PMC9482082/

^[2] World Health Organization. (7 August, 2024). The top 10 causes of death. [website]. Accessed 16 December, 2024. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death

^[3] Ference, B. A., Ginsberg, H. N., Graham, I., Ray, K. K., Packard, C. J., Bruckert, E., ... & Catapano, A. L. (2017). Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European heart journal, 38(32), 2459-2472. https://academic.oup.com/eurheartj/article/38/32/2459/3745109

^[4] Ferhatbegović, L., Mršić, D., Kušljugić, S., & Pojskić, B. (2022). LDL-C: the only causal risk factor for ASCVD. Why is it still overlooked and underestimated?. Current Atherosclerosis Reports, 24(8), 635-642. https://link.springer.com/article/10.1007/s11883-022-01037-3

^[5] Mundi, S., Massaro, M., Scoditti, E., Carluccio, M. A., Van Hinsbergh, V. W., Iruela-Arispe, M. L., & De Caterina, R. (2018). Endothelial permeability, LDL deposition, and cardiovascular risk factors—A review. Cardiovascular research, 114(1), 35-52. https://pmc.ncbi.nlm.nih.gov/articles/PMC7729208/

^[6] Jebari-Benslaiman, S., Galicia-García, U., Larrea-Sebal, A., Olaetxea, J. R., Alloza, I., Vandenbroeck, K., ... & Martín, C. (2022). Pathophysiology of atherosclerosis. International journal of molecular sciences, 23(6), 3346. https://www.mdpi.com/1422-0067/23/6/3346

^[7] Arnett, D. K., Blumenthal, R. S., Albert, M. A., Buroker, A. B., Goldberger, Z. D., Hahn, E. J., ... & Ziaeian, B. (2019). 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of cardiology, 74(10), e177-e232. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000678

Additional Reading:

Popa-Fotea, N. M., Ferdoschi, C. E., & Micheu, M. M. (2023). Molecular and cellular mechanisms of inflammation in atherosclerosis. Frontiers in Cardiovascular Medicine, 10, 1200341. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1200341/full