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Cholesterol and CVD risk: beyond quality and density, time to look at typology and number

Cholesterol is used by the body to make hormones and stabilize cellular membranes. But when low-density lipoprotein (LDL) cholesterol levels are too high, cholesterol can accumulate inside blood vessels, forming deposits called plaques. These plaques can eventually lead to blood vessel blockages that cause heart attacks or strokes. HDL cholesterol helps remove cholesterol from blood vessels. For decades, high-density lipoprotein (HDL) cholesterol has been dubbed “good cholesterol” because of its role in moving fats and other cholesterol molecules out of artery walls. People with higher HDL cholesterol levels tend to have lower rates of cardiovascular disease, studies have shown. But recent studies have come to mixed conclusions about the association between HDL cholesterol levels and CVD risk, indicating that also high HDL may pose a threat to blood vessels. According to the CDCs, heart disease is the leading cause of death in the United States. More than 13% of adults have high total cholesterol levels, and more than 20% have what’s currently considered low levels of HDL cholesterol.

Recent studies deemed that the old strict HDL/LDL division as “good” or “bad” cholesterol has to be upgraded; in this process, considering additional biologic factors might improve knowledge. For example, UT Southwestern scientists, led by associate professor Anand Rohatgi at the Department of Internal Medicine, have analyzed data on more than 15,000 people to better understand the association between HDL cholesterol, heart attacks, and strokes in diverse populations. They found that the number of HDL particles is a more reliable predictor of heart attack and stroke risk than the standard HDL cholesterol metric. Moreover, they found that among black people, neither HDL measurement was significantly associated with heart attack. Previous studies have looked at HDL levels in the population as a whole. But scientists know that sometimes biology differs by gender and race, so researchers thought it was important to separately tease apart what’s happening in those populations, as well as how HDL is associated with stroke, which has been understudied.

Therefore, they pooled together information on people who had participated in four large, nationwide studies called MESA, ARCS, DHS and PREVED. Overall, the studies included 15,784 people followed over an average of 8 to 12 years. Of the participants, 54% were male, 22% were black and their average age was 56 years. By combining all these large existing cohorts, scientists had enough numbers to look at these populations that had been understudied in the past. In addition, the data included two different measurements of HDL: HDL-P levels, tallying how many particles of HDL are circulating in the blood. HDL-C levels, the standard test, instead quantifying how much total HDL cholesterol is inside those particles. Since the number of HDL particles may vary with regards to how much cholesterol they contain, the two measurements can be quite different and are only moderately correlated. In the study, people with the highest HDL-P levels had a 37% lower risk of heart attack and a 34% lower risk of stroke than those who had the lowest HDL-P levels.

In women, this association was stronger – those with the highest HDL-P levels had a 49% reduction in heart attacks and 46% reduction in stroke. While HDL-C predicted heart attack risk in the overall pool of people as well as in women, it was not associated with stroke. When the researchers homed in on black participants, the results were different – neither HDL-C nor HDL-P was linked to a black person’s risk of heart attack. Dr. Katvina Singh, first author of the research, commented: “If you’re white, low HDL cholesterol is still a powerful predictor of heart attack and stroke risk, and that has not changed. But if you’re not white, it’s not that straightforward. These risk markers are really relevant in everyday primary care and cardiology. Doctors use cholesterol levels to make decisions like whether a patient goes on medication or not”. The team is planning future studies on the functionality of HDL particles among black people, how HDL-P may be used clinically, and whether HDL-P might be associated with specific subtypes of strokes.

A later publication of a joint team from the Johns Hopkins Institutes, University of Minnesota and Monash University at Melbourne, instead, published data speculating that the so-called remnant cholesterol may predict cardiovascular disease beyond the classical markers like LDL and ApoB. The team pooled data from 17 532 heart disease-free individuals from the ARC study (n=9748), the MESA study (n=3049) and the CARDYA study (n=4735). Remnant cholesterol was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. There were 2143 cardiovascular events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log remnant cholesterol was associated with higher cardiovascular risk. Two studies published last June, finally, found influence of remnant cholesterol on mortality in patients with type 2 diabetes and incident kidney disease, along with risk for chronic kidney failure. This last association seemed molre likely in women than in men.

This remarks again the importance of gender in deciphering the differential metabolic effects of “cholesterols” inside the current concept of cardiovascular risk. According to these latest discoveries, hence, a better understanding of how HDL, LDL and other types of cholesterol can help predict disease, and how that association varies among populations, is pivotal to lowering global rates of cardiovascular diseases.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Rohatgi A et al. Circulation 2021; 143(23):2293-2309.

Yu D et al. J Clin Endocr Metab. 2021 Jul 22:dgab533.

Yan P, Xu Y, Miao Y et al. Acta Diabetol. 2021 Jun 28.

Castañer O et al. J Am Coll Cardiol. 2020; 76(23):2712. 

Singh K et al. Circulation. 2020 Aug; 142(7):657-669.

Thakkar H et al. Lipids Health Dis. 2020; 19(1):75.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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