What are the health problems caused by high cholesterol?

Unhealthy levels of cholesterol and other lipids are called dyslipidemia. The levels that are considered unhealthy have changed as experts study the effects of different components of the lipid, cholesterol, and lipoprotein system.^1,2 People with premature coronary heart disease (CHD) are more likely to have abnormal levels of cholesterol compared to people without CHD. Elevated total cholesterol (TC), low levels of HDL cholesterol (HDL-C), and increased levels of non-HDL-C have all been shown to be associated with an increased risk of CHD. TC and HDL-C are measured in standard cholesterol screening tests and low-density lipoprotein cholesterol (LDL-C; a portion of non-HDL-C) is calculated from those results. Although other lipids and lipoproteins have been shown to elevate risk of CHD, these measurements have not been shown to be better at predicting CHD risk compared to standard measurements of cholesterol.³

Excess cholesterol leads to the development of atherosclerosis, a buildup of plaque on the blood vessel wall that narrows the vessel compromising healthy blood flow and tissue perfusion. Observational studies have demonstrated that TC is positively associated with ischemic heart disease and stroke rates and that this relationship is continuous as blood concentrations of cholesterol increase.^4,5 Randomized controlled trials and meta-analyses that examined the effects of statin therapy versus controls have confirmed these findings and demonstrated the beneficial effects of statin therapy on the prevention and treatment of atherosclerotic cardiovascular disease (CVD).⁶

One-third of strokes are caused by large artery extracranial or intracranial atherosclerosis.⁷ Because of the known association between elevated cholesterol and the development of atherosclerosis, the management of dyslipidemia and other vascular risk factors like hypertension is a mainstay of medical therapy used for prevention of this type of stroke.  The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial enrolled 4,731 patients with a history of stroke or transient ischemic attack and LDL-C levels between 100 mg/dL and 190 mg/dL and randomly assigned them to receive atorvastatin 80 mg or placebo.⁸  Over a 5-year follow-up, the risk of recurrent stroke was lower among those taking atorvastatin (11.2%) compared to placebo (13.1%) (5-year absolute reduction in risk 2.2%; adjusted hazard ratio, 0.84, 95% confidence interval [CI] [0.71 – 0.99], p=0.03; unadjusted p=0.05). The rate of hemorrhagic stroke was increased among people who took the statin, but there was no difference in mortality compared to placebo, and no difference in the efficacy of statin use based on the mechanism of stroke.

Data supporting a link between cholesterol levels and peripheral vascular disease is less robust, based primarily on prevalence studies. In the Spanish Familial Hypercholesterolemia Cohort Study (n=2,752 with molecularly diagnosed familial hypercholesterolemia [FH] and 993 unaffected relatives), peripheral artery disease (PAD) was more prevalent among participants with FH (1.4%) compared to their unaffected relatives (0.2%), p<0.001.⁹ Baseline cholesterol levels were not available in this study that could have directly linked cholesterol levels with relative risk of PAD.

Allison et al. studied 6,814 people without clinical CVD in the Multiethnic Study of Atherosclerosis (MESA) who underwent standardized testing for the presence of PAD using the ankle-brachial index.¹⁰ Of the 275 participants with PAD, 127 (46.2%) had dyslipidemia compared to 2,128 (33.5%) of the 6,378 without PAD (p<0.01). Dyslipidemia was defined as TC/HDL-C ratio >5.0 or the participant used medication to lower cholesterol. For reasons that are not yet fully understood, the risk of PAD is highest among individuals of African American ethnicity.¹¹ This was corroborated in the data from MESA.¹⁰

Prevalence studies^11,12 have demonstrated that in addition to cigarette smoking, diabetes, and hypertension, elevations in TC and the combination of low levels of HDL-C and high levels of triglycerides are risk factors for PAD.  The TC/HDL-C ratio was also shown to be the strongest lipid measurement of risk for the development of PAD in the Physicians Health Study (n=14,916). The relative risk for those in the highest vs. lowest quartile of TC/HDL-C was 3.9 (95% CI [1.7 – 8.6]).¹³ 

Treatment of hyperlipidemia may decrease the risk of progression of PAD and the incidence of intermittent claudication. In the Heart Protection Study (total n=20,536 of which 6,748 had PAD), patients were randomized to receive simvastatin 40 mg daily or placebo. The absolute reduction in first major vascular event was 63 (standard error [SE]11) per 1,000 patients with PAD and 50 (SE 7) per 1,000 participants without pre-existing PAD. Overall, among all participants, there was a 16% (5 – 25) relative reduction in the rate of first peripheral vascular event following randomization (479 [4.7%] simvastatin vs. 561 [5.5%] placebo), regardless of baseline LDL-C.¹⁴

Epidemiological studies have demonstrated that patients with high blood pressure often also have high levels of cholesterol.^15–17 However, it is not yet clear if the presence of high cholesterol causes high blood pressure. Several studies have attempted to determine the relationship between these distinct cardiovascular risk factors to better guide treatment and prevention efforts.

^References

1. National Cholesterol Education Program. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. https://web.archive.org/web/20050530005143/http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed November 30, 2019.
2. Grundy S, Stone N, Beam C, Birtcher KK, Harm PD. 2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019; 73 (24): e285-e350.
3. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009; 119 (7): 931-939.
4. MacMahon SW, Macdonald GJ, Blacket RB. Plasma lipoprotein levels in treated and untreated hypertensive men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. Arteriosclerosis 1985; 5 (4): 391-396.
5. Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ 1991; 303 (6797): 276-82.
6. Cholesterol Treatment Trialists Collaboration. https://www.cttcollaboration.org. Accessed December 2, 2019. 
7. Esenwa C, Gutierrez J. Secondary stroke prevention : challenges and solutions. Vasc Heal Risk Manag 2015; Aug 7 (11): 437-450.
8. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355 (6): 549-559.
9. Perez de Isla L, Alonso R, Mata N, et al. Coronary heart disease, peripheral arterial disease, and stroke in familial hypercholesterolaemia: insights from the SAFEHEART registry (Spanish Familial Hypercholesterolaemia Cohort Study). Arter Thromb Vasc Biol 2016; 36 (9): 2004-2010.
10. Allison MA, Criqui MH, McClelland RL, et al. The effect of novel cardiovascular risk factors on the ethnic-specific odds for peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006; 48 (6): 1190-1197.
11. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States. Circulation 2004; Aug 10 (6): 738-743.
12. Murabito JM, Evans JC, Nieto K, Larson MG, Levy D, Wilson PWF. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Hear J 2002; 143 : 961-965.
13. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285 (19): 2481-2485.
14. Heart Protection Study Collabortaive. Randomized trial of the effects of cholesterol- lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007; 45 (4): 645-655.
15. Laurenzi M, Mancini M, Menotti A, et al. Multiple risk factors in hypertension: results from the Gubbio study. J Hypertens Suppl 1990; 8 (1): S7-12.
16. MacMahon S, Duffy S, Rodgers A, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: A meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370 (9602): 1829-1839.
17. Castelli WP, Anderson K. A population at risk: prevalence of high cholesterol levels in hypertensive patients in the Framingham study. Am J Med 1986; 80 (2 SUPPL. 1): 23-32.