Let’s begin with a case. The patient is a 67-year-old female with a past medical history of hypothyroidism referred to your Cardiology Clinic by her primary care physician for cardiovascular disease risk stratification. She was found to have mild coronary artery calcification (CAC) on CT with an Agatston score of 88. The patient has a strong family history of heart disease, including her father who died of myocardial infarction sometime in his fifties and her brother who required six-vessel coronary artery bypass graft (CABG) at the age of 58. The patient is asymptomatic and denies chest pain and dyspnea on exertion. She does not smoke and does not have diabetes. Her lipid panel is as follows:
Total cholesterol: 214 mg/dL
HDL-C: 103 mg/dL
LDL-C: 67 mg/dL
How do you approach risk stratification for this patient? How do you treat this patient (if treatment is even warranted at all)? To answer these questions, let’s review the basics of high-density lipoproteins and how they may be contributing to the pathophysiology in this patient.
High-density lipoproteins (HDL) are a class of circulating particles in humans with multiple subpopulations that vary in their lipid and protein composition. The cholesterol contained within HDL particles, termed HDL cholesterol or HDL-C, is a measurable biomarker that is inversely correlated with the risk of atherosclerotic cardiovascular disease (ASCVD). There are a plethora of studies that have established the inverse relationship of HDL cholesterol and ASCVD risk.1,2 As an example, using data from the Framingham Heart Study, researchers found that the risk of myocardial infarction (MI) increases by about 25% for every 5 mg/dL decrement in HDL cholesterol below the median value for males and females.3 HDL particles protect against atherosclerosis via multiple mechanisms, such as removing excess cholesterol from macrophages (i.e. macrophage cholesterol efflux), enhancing endothelial function, and promoting anti-inflammation. However, research has not demonstrated that low HDL cholesterol levels are causative of increased ASCVD risk. Mendelian randomization, an epidemiologic method that employs genetic information to answer questions of causality, has been the main tool used to refute low HDL cholesterol as a causative agent of ASCVD. One study using Mendelian randomization looked at individuals with genetic variants that confer abnormally low levels of HDL cholesterol. Results from this study suggested that low HDL levels indeed are not a causative agent of MI.4 Another study looked at individuals with genetic variants that confer abnormally high levels of HDL cholesterol and found that they do not have lower risk of MI, also refuting the causality of HDL cholesterol.5 Additional studies have investigated therapies that raise HDL cholesterol levels as a means of ASCVD risk reduction and found no significant benefit.6,7,8 In fact, a 2009 meta-analysis of 108 randomized trials showed that treatment-induced elevations in HDL cholesterol did not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths.9 Thus, current treatment guidelines for ASCVD risk reduction target reducing low density lipoprotein (LDL) cholesterol levels rather than raising HDL cholesterol levels.
The puzzling conclusion that increased HDL cholesterol is associated with lower ASCVD risk, yet treatment-induced elevations in HDL cholesterol have shown no risk reduction is likely due to the lack of causality and the complexity of HDL subpopulations.10 This underscores the fact that HDL cholesterol should be viewed as a biomarker of ASCVD risk rather than a targetable entity for treatment. Further characterization of HDL subpopulations and their unique functionalities may be the key to developing targeted HDL therapies that could increase or decrease specific types of HDL particles and thereby reduce ASCVD risk.
Bearing in mind the caveats of using HDL cholesterol as a biomarker of ASCVD risk, measuring HDL cholesterol has some important clinical implications.11 In patients with low HDL cholesterol (<50 mg/dL), treatment guidelines suggest aggressive LDL lowering therapy (e.g. high-dose statins) if LDL cholesterol is elevated. In patients with high HDL cholesterol (>60 mg/dL) and thus lower risk of atherosclerotic disease, treatment guidelines suggest similar LDL- lowering therapy if LDL cholesterol is elevated. The treatment recommendations for patients with high HDL cholesterol are the same as for patients with low HDL cholesterol, based on the lack of evidence supporting less aggressive LDL lowering therapy. Lastly, there exists a third group of patients: those with significantly elevated HDL cholesterol (>100 mg/dL). Much less is known about this group of patients, and there is a paucity of established guidelines for their management.
Although many observational studies have demonstrated that high HDL cholesterol levels are associated with a lower risk of ASCVD, other studies suggest the existence of a “sweet spot” of HDL cholesterol, above which the risk of ASCVD paradoxically increases. A 2017 observational study by Madsen and colleagues published in the European Heart Journal found that very high HDL cholesterol is associated with higher all-cause mortality in both men and women.12 In fact, the authors showed that the relationship between HDL cholesterol and all-cause mortality is U-shaped. The lowest all-cause mortality was associated with HDL cholesterol concentrations of 73 mg/dL in men and 93 mg/dL in women and there was increased all-cause mortality at both very low and very high HDL cholesterol concentrations. When compared with the lowest all-cause mortality group of women, the adjusted hazard ratios for women with HDL cholesterol 116-134 mg/dL was 1.10 (95% CI: 0.83-1.46) and for women with HDL cholesterol >135 mg/dL was 1.68 (95% CI: 1.09-2.58).
The pathophysiology of this paradoxical increase in cardiovascular risk with very elevated HDL cholesterol levels remains unclear, but it is likely due to the impaired functionality of HDL particles. Ansell and colleagues showed that patients with coronary artery disease and very elevated HDL cholesterol levels (95 +/- 14 mg/dl) have HDL particles that are more pro-inflammatory compared to patients with coronary artery disease and normal HDL cholesterol levels (57 +/- 13 mg/dl).13 In these conditions of concurrent ASCVD and elevated HDL cholesterol, the patient is said to have “dysfunctional” HDL, a condition in which the HDL particles are large, have reduced anti-inflammatory proteins, and have impaired antiatherogenic properties.14 Dysfunctional HDL is thought to have a wide range of etiologies, including genetic causes, states of chronic inflammation, and hypothyroidism. Regardless of the etiology, whether it be hereditary or acquired, a patient with very elevated HDL cholesterol levels merits attention. Dysfunctional HDL again illustrates the need for better characterization of HDL subpopulations and their unique functionalities. This characterization will allow researchers the ability to develop targeted therapies aimed at reducing dysfunctional HDL particles and/or increasing beneficial HDL particles.
Returning to the case of our patient, she was found to have elevated HDL cholesterol to 103 mg/dL. Of note, her HDL cholesterol level has been constant over many years, staying within the range of 100-110 mg/dL. The literature suggests that our patient has dysfunctional HDL, as she has evidence of ASCVD on CT with calcium and a persistently elevated HDL cholesterol level. Her strongly positive family history of ASCVD is concerning for a hereditary etiology of dysfunctional HDL. The patient’s brother required six-vessel CABG at 58 years of age and he presented with none of the known ASCVD risk factors. While this evidence suggests a genetic cause of dysfunctional HDL, our patient also carries a diagnosis of hypothyroidism that puts her at risk of acquired dysfunctional HDL. Although the exact mechanism remains unclear, hypothyroidism has been shown to elevate the HDL cholesterol level and may lead to a state of dysfunctional HDL.15
The question remains: how should this patient be managed? Many studies advocate for the accurate diagnosis of dysfunctional HDL; however, there are currently no established guidelines for the primary prevention of ASCVD in these patients.16 In our patient’s case, the decision was made to treat her with a primary prevention regimen of a high-intensity statin and daily low-dose aspirin. Additionally, the patient was started on ramipril 1.25 mg PO daily for further risk reduction. This case illustrates why more research is essential: to advance HDL cholesterol from a biomarker to a targetable treatment option and to establish consensus guidelines for the management of patients with dysfunctional HDL.
By Matthew Auda is a 2nd year medical student at NYU Grossman School of Medicine
Reviewed by Michael Tanner, MD, associate editor, Clinical Correlations
Image courtesy of Wikimedia Commons, source: https://commons.wikimedia.org/wiki/File:The_new_shape_of_cholesterol_colored_version.jpg
- Emerging Risk Factors Collaboration; Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.
- Acharjee S, Boden WE, Hartigan PM, et al. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). J Am Coll Cardiol. 2013;62(20):1826-1833. doi: 10.1016/j.jacc.2013.07.051. Epub 2013 Aug 21. PMID: 23973693; PMCID: PMC5661970. https://pubmed.ncbi.nlm.nih.gov/23973693/
- Castelli WP. Cardiovascular disease and multifactorial risk: challenge of the 1980s. Am Heart J. 1983;106(5 Pt 2):1191-200. doi: 10.1016/0002-8703(83)90174-6. PMID: 6637784. https://pubmed.ncbi.nlm.nih.gov/6637784/
- Haase CL, Tybjærg-Hansen A, Qayyum AA, Schou J, Nordestgaard BG, Frikke-Schmidt R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012;97(2):E248-256. doi: 10.1210/jc.2011-1846. Epub 2011 Nov 16. PMID: 22090275. https://pubmed.ncbi.nlm.nih.gov/22090275/
- Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380(9841):572-580. doi: 10.1016/S0140-6736(12)60312-2. Epub 2012 May 17. Erratum in: Lancet. 2012 Aug 11;380(9841):564. PMID: 22607825; PMCID: PMC3419820.
- Boden WE, Probstfield JL, Anderson T, et al.; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–2267. doi: 10.1056/NEJMoa1107579. https://www.scirp.org/%28S%28vtj3fa45qm1ean45vvffcz55%29%29/reference/referencespapers.aspx?referenceid=2488861
- Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–212. doi: 10.1056/NEJMoa1300955.
- Schwartz GG, Olsson AG, Abt M, et al; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099. doi: 10.1056/NEJMoa1206797.
- Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92. doi: 10.1136/bmj.b92. PMID: 19221140; PMCID: PMC2645847.
- Rosenson RS. The high-density lipoprotein puzzle: Why classic epidemiology, genetic epidemiology, and clinical trials conflict? Arterioscler Thromb Vasc Biol. 2016;36(5):777-782. doi: 10.1161/ATVBAHA.116.307024. Epub 2016 Mar 10. PMID: 26966281.
- Rosenson RS, Durrington P. HDL cholesterol: Clinical aspects of abnormal values. UpToDate. Waltham, MA: UpToDate Inc.
- Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38(32):2478-2486. doi: 10.1093/eurheartj/ehx163. PMID: 28419274.
- Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation. 2003;108(22):2751-2756. doi: 10.1161/01.CIR.0000103624.14436.4B. Epub 2003 Nov 24. PMID: 14638544.
- Rosenson RS, Brewer HB Jr, Ansell BJ, et al. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol. 2016;13(1):48-60. doi: 10.1038/nrcardio.2015.124. Epub 2015 Sep 1. PMID: 26323267; PMCID: PMC6245940.
- Su X, Peng H, Chen X, Wu X, Wang B. Hyperlipidemia and hypothyroidism. Clin Chim Acta. 2022;527:61-70. doi: 10.1016/j.cca.2022.01.006. Epub 2022 Jan 14. PMID: 35038435.
- Smith JD. Dysfunctional HDL as a diagnostic and therapeutic target. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):151-155. doi: 10.1161/ATVBAHA.108.179226. Epub 2009 Aug 13. PMID: 19679832; PMCID: PMC2809786.