Low density lipoprotein natural history, prognosis and complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]


The natural history and the prognosis of high LDL concentrations are directly associated with the complications of atherosclerosis, namely cardiovascular disease (CVD) which is the most common cause of mortality worldwide. Classically, elevated LDL concentration has been associated with significantly increased rates of coronary artery disease (CAD). However, emerging evidence has demonstrated that an elevated concentration of LDL is also strongly associated with insulin resistance as well as other forms of ischemic vascular diseases. The role of elevated levels of LDL in the development of ischemic complications, such as stroke, peripheral arterial disease, carotid atherosclerosis, and renovascular injury, has also been validated. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations.


The natural history and prognosis of patients with elevated LDL are directly related to the complications associated with dyslipidemia. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations. The majority of patients with elevated plasma LDL and atherosclerosis who are left untreated often develop manifestations of cardiovascular disease (CVD), the most common cause of death worldwide. Elevated LDL is also frequently associated with other cardiovascular risk factors, such as diabetes mellitus, hypertension, and low HDL that lead more rapidly to the development of cardiovascular disease.[1][2] Shown below is a list of complications associated with elevated concentrations of LDL and atherosclerosis:

Coronary Artery Disease

  • Dyslipidemia caused by elevated LDL is a major risk factor for coronary artery disease (CAD) and often regarded as a prerequisite.[3]
  • There is a direct association between cardiovascular death and duration of elevated plasma LDL levels.[4]
  • An increase of LDL by 10 mg/dL is associated with a 12% increase in CVD risk in both genders.
  • Accumulating evidence has proved the role of elevated LDL in the development of atherosclerosis and has demonstrated that lowering LDL attributes to significant reductions (30-37%) in CAD.[5]

Diabetes Mellitus and Insulin Resistance

  • Elevated concentrations of small dense LDL is often observed among patients before development of insulin resistance.[6]
  • The majority of patients with elevated LDL have other components of the metabolic syndrome, such as hypertriglyceridemia, hypertension, and insulin resistance.[6]


  • The association between elevated LDL and stroke has been observed, but the association has not been as strongly established as in the case of coronary artery disease.[7]
  • Nonetheless, statin therapy is important in cerebrovascular events, especially among patients with other manifestations of atherosclerosis, namely coronary artery disease. Statin therapy may significantly reduce the rate of ischemic stroke by approximately 20-30%.[7][8]
  • The true relation between elevated LDL levels and ischemic stroke as a complication is yet to be delineated.

Carotid Artery Atherosclerosis

  • Elevated LDL is the primary risk factor for the initiation and development of carotid artery atherosclerosis.
  • A reduction of LDL concentrations by at least 25% is associated with a significant reduction in the radiographic progression of carotid atherosclerosis

Renovascular Disease

  • Elevations of LDL is hypothesized to be the major initiator of renovascular injury associated with renal artery stenosis.[9]
  • Oxidation of high concentrations of LDL, along with an increasein local and systemic oxidative stress, promotes the generation of reactive oxygen species (ROS) that cause vasoconstriction and worsen renal ischemia.[10]
  • Emerging evidence currently favors the pharmacologic management of dyslipidemia for the treatment of renal artery stenosis compared to angioplasty.[9]

Peripheral Arterial Disease

  • Elevated LDL is a risk factor for the development of peripheral arterial disease (PAD) and contributes to its progression and other manifestations of CVD.
  • The aggressive management of atherosclerosis is a primary goal in the management of PAD, given the abundance of data to suggest that LDL normalization improves femoral arterial atherosclerosis and alters the natural history of PAD.


  • The Framingham study demonstrated that elevated LDL is associated with non-CAD-death among both genders.[2]


  1. Stamler J, Vaccaro O, Neaton JD, Wentworth D (1993). "Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial". Diabetes Care. 16 (2): 434–44. PMID 8432214.
  2. 2.0 2.1 Gordon T, Kannel WB, Castelli WP, Dawber TR (1981). "Lipoproteins, cardiovascular disease, and death. The Framingham study". Arch Intern Med. 141 (9): 1128–31. PMID 7259370.
  3. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM; et al. (2011). "Heart disease and stroke statistics--2011 update: a report from the American Heart Association". Circulation. 123 (4): e18–e209. doi:10.1161/CIR.0b013e3182009701. PMID 21160056.
  4. Rader DJ, Cohen J, Hobbs HH (2003). "Monogenic hypercholesterolemia: new insights in pathogenesis and treatment". J Clin Invest. 111 (12): 1795–803. doi:10.1172/JCI18925. PMC 161432. PMID 12813012.
  5. Sharma SB, Garg S (2012). "Small dense LDL: risk factor for coronary artery disease (CAD) and its therapeutic modulation". Indian J Biochem Biophys. 49 (2): 77–85. PMID 22650003.
  6. 6.0 6.1 Solano MP, Goldberg RB (2006). "Management of dyslipidemia in diabetes". Cardiol Rev. 14 (3): 125–35. doi:10.1097/01.crd.0000188034.76283.5e. PMID 16628021.
  7. 7.0 7.1 "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet. 344 (8934): 1383–9. 1994. PMID 7968073.
  8. "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group". N Engl J Med. 339 (19): 1349–57. 1998. doi:10.1056/NEJM199811053391902. PMID 9841303.
  9. 9.0 9.1 Annigeri RA (2012). "Medical therapy is best for atherosclerotic renal artery stenosis: Arguments for". Indian J Nephrol. 22 (1): 1–4. doi:10.4103/0971-4065.91177. PMC 3263056. PMID 22279335.
  10. Meier P, Rossert J, Plouin PF, Burnier M (2007). "Atherosclerotic renovascular disease: beyond the renal artery stenosis". Nephrol Dial Transplant. 22 (4): 1002–6. doi:10.1093/ndt/gfl784. PMID 17210599.

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