High density lipoprotein natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]; Vendhan Ramanujam M.B.B.S [4]


Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risks,[1][2][3] low circulating levels of HDL-cholesterol have been associated with the development of coronary artery disease, particularly when it is accompanied by other coronary risk factors.[4][5][6] The protective role of high HDL levels against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differently associated with cardiovascular risks. Many case-control and prospective studies have demonstrated that the HDL2 sub fraction and the plasma apo A-I concentration are better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3.[7] The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.[8] In addition to its prognotic role in CAD, low HDL levels have been associated with diseases and complications involving the neurological, renal, and liver systems as well as sepsis and carcinoma.

Low High-Density Lipoprotein as a Prognostic Factor

Low HDL has been evaluated as a possible prognostic factor in the following conditions:

Coronary Artery Disease

The inverse relation of HDL to either the presence or development of coronary artery disease (CAD) is well-established;[9] in fact, for every 1% decrease in HDL concentration, there is a 2-3% increase in the risk of development of CHD.[10] Studies on different populations supported low HDL as a significant cardiovascular risk factor as well as a prognostic factor, either independently or along with other physical and biochemical metrics. Low levels of HDL-cholesterol, which may reflect increased catabolism of triglyceride-enriched HDL particles, appear to interact with hypertriglyceridemia to increase the coronary risk.[11][12] Plaque rupture, besides its correlation with high total cholesterol (TC), is also shown to be related to low HDL-cholesterol and an elevated TC/HDL-C ratio.[13] Studies on the relationship between low HDL levels and CAD are as follows:

  • Based on data from the Framingham Heart Study, the risk for myocardial infarction was found to increase by 25 percent for every 5 mg/dL (0.13 mmol/L) decrement in serum HDL-cholesterol, below the median values for both men and women.[4] According to the study, the relative risk of death due to cardiovascular and coronary artery disease for men in the first HDL-cholesterol quintile (less than 35 mg/dL) as compared to the top quintile (greater than 54 mg/dL) is 3.6 and 4.1 respectively and for women the corresponding values were 1.6 and 3.1, comparing the bottom HDL-cholesterol quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl).
  • The Lipoprotein and Coronary Atherosclerosis Study (LCAS) which studied patients with mild to moderate LDL-cholesterol elevation found that the patients who also had low HDL-cholesterol at baseline had more CAD progression than patients with higher HDL-cholesterol.[14]
  • Framingham Risk Assessment counts HDL values above 60 mg/dL (1.5 mmol/L) as a negative risk factor.[5]
  • Studies have shown that in patients with known coronary artery disease, HDL-cholesterol levels are predictive of coronary events over a broad range of LDL-cholesterol levels. The LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial[15] and the CARE (Cholesterol and Recurrent Events) trial[16] have shown that reduced serum HDL-cholesterol levels strongly predicted acute coronary events in patients with LDL-cholesterol less than 125 mg/dL compared to those with levels above 125 mg/dL. There was a significant reduction in the event rate in patients with LDL-cholesterol <125 mg/dL for every 10 mg/dL rise in HDL-cholesterol compared to those with LDL-cholesterol levels more than 125 mg/dL. A similar relationship between the levels of HDL-cholesterol and LDL-cholesterol was also shown in the Treating to New Targets (TNT) trial.[17]
  • The finding of very low HDL levels among one-fifth of patients with NSTEMI ACS added to a greater burden of atherosclerosis and a higher risk of mortality.[18]
  • A study conducted in a European population revealed that patients carrying at least one polymorphic allele of the paraoxonase2 (PON2) gene along with low HDL represent a category of subjects at a higher risk for the development of acute myocardial infarction with a worse prognosis.[19]
  • A 2011 population based study with individual-participant-data (over 200,000 individuals) meta-analysis of 23 studies in the Asia-Pacific region revealed that a low level of HDL cholesterol was seen significantly more often in Asians than non-Asians (33.1 versus 27.0%). Even the prevalence of isolated low HDL-cholesterol was significantly higher in Asians (22.4 versus 14.5 %). In all individuals, there was a significant correlation between low HDL cholesterol and cardiovascular events. Particularly in Asians, the isolated low levels of HDL cholesterol were strongly associated with CAD risk similar to low levels of HDL cholesterol combined with other lipid abnormalities. This study suggested that isolated low HDL cholesterol in Asians is a distinct phenotype, which is strongly associated with an increased risk of CAD.[20]
  • More recently low HDL-cholesterol was found to be the most powerful lipid parameter for predicting the risk and the clinical outcome of CAD in a Han Chinese population.[21]

The Multi-ethnic Study of Atherosclerosis (MESA) adds to the concept that the inverse relationship between HDL and cardiovascular risks may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.[22] HDL2 subfraction and apo A-I are reported to be better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3 in some studies,[7] while other reports have shown similar associations of total HDL and HDL3 with coronary artery disease (CAD) as HDL2 and apo A-I.[23] Polymorphisms in phospholipid transfer protein (PLTP) are also shown to be associated with increased concentrations of smaller, cholesterol-depleted HDL particles and a lower cardiovascular event rate.[24] Despite the established crude association between HDL and cardiovascular risks, Mendelian randomization analyses, JUPITER trial, and studies in Tangier disease failed to demonstrate a cause-effect relationship.[25][26][27][28]

CAD in Pediatric Populations

Data is scarce about the contribution of HDL to CAD in the pediatric population due to the rarity of cases. A prospective follow-up study in pediatric cardiac transplant recipients showed that, although pravastatin improved the HDL2 concentrations in the treatment group, it failed to normalize serum triglyceride and prevent the progression of vasculopathy in some of the patients. It also suggested a predictive role of low HDL-C and high apoB-100/apoA-I ratio for the development of vasculopathy.[29]

Premature CAD

Premature CAD is usually defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age. Numerous studies of the 20th century from both Middle East and US population have reported low HDL in over 19% to 52 % of premature CAD patients.[30][31][30][32][33][34] In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study that examined aortas and coronary arteries from autopsies of healthy 15 to 35 year old persons, a negative association of high HDL with both fatty streaks and raised lesions in the aorta and right coronary artery was seen, particularly after the age of 25. Post-hoc analyses of two randomized trials in the past 10 years have shown low HDL levels as predictors of coronary events in patients with known CAD. Analysis of 13,173 patients in the LIPID and CARE trials found that low serum HDL cholesterol was a significantly stronger predictor of CAD events in patients with an LDL-cholesterol <125 than ≥125 mg/dL (3.2 mmol/L).[35] For a 10 mg/dL (0.26 mmol/L) increase in HDL-cholesterol the event rate decreased by 29 percent in those with LDL-cholesterol <125 mg/dL (3.2 mmol/L) compared to 10 percent in those with an LDL-cholesterol ≥125 mg/dL (3.2 mmol/L). Post hoc analysis of the Treating to New Targets trial (TNT) in which nearly 10,000 patients with established CAD was treated with either high or low dose statin therapy revealed that HDL cholesterol levels were predictive of major cardiovascular events. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter.[36]

An investigation of the effects of baseline HDL cholesterol on the outcomes of 1032 patients who underwent drug-eluting stent implantation for acute coronary syndrome showed a higher rate of incidences of mortality and major adverse cardiac events at 30 days in low HDL than the high HDL cholesterol group. At 1 year, more deaths and major adverse cardiac events occurred in the low HDL cholesterol group. Multivariate analysis finally showed that low HDL cholesterol is a key predictor of major adverse cardiac events and death at 1 year.[37]

But not all disorders associated with low HDL cholesterol are accompanied by a predisposition to premature CAD.[38] Examples in which there is not a strong association with atherosclerosis includes patients with LCAT deficiency,[39] and patients with the apo A-I Milano variant.[40]

CAD in Elderly

Low HDL in elderly age group (above 60 and 65 years in men and women respectively) is a known high risk factor of CAD.[41] Prevalence of around 70% of increased serum LDL cholesterol and 70% of decreased serum HDL cholesterol have been reported in elderly patients with atherosclerotic vascular disease.[42] The Framingham Heart Study and the Systolic Hypertension in the Elderly Program (SHEP) also found that both high LDL and low HDL cholesterol levels were significant CAD risk factors in elderly subjects.[43][44] Low HDL can also be a predictor of mortality in elderly CAD patients. In a prospective cohort study that included a total population of 2527 women and 1377 men, for each 1-unit increase in the total cholesterol/HDL-cholesterol ratio, a 17% increase in the risk of CAD death was reported.[45]

CAD in Women

Low HDL levels can be considered a prognostic factor of CAD in women. 40% to 50% of women classified as being at intermediate risk using the Framingham risk model were reclassified into either higher or lower risk categories, emphasizing the importance of HDL cholesterol level along with other factors in CAD development among women.

The Reynolds risk score was developed and validated using data available from nearly 25,000 healthy women followed up prospectively for incidence of CAD and stroke during a median of 10.2 years and it included HDL cholesterol levels along with other factors.[46]

Weight cycling (repeated weight loss and weight gain) in women is known to carry an increased risk of death from CAD. This may be related to a significant reduction in HDL cholesterol concentration during each cycle.[47]

In postmenopausal women, the degree of coronary atherosclerosis has been linked to dysregulation of the TG/HDL metabolism. Subpopulations of both triglyceride rich and HDL lipoproteins have been found to be better predictors of CAD than triglyceride and HDL cholesterol concentrations.[48]

In women with polycystic ovarian syndrome (PCOS), most studies have demonstrated associated low HDL cholesterol.[49][50] In one study , components of the metabolic syndrome including low HDL and insulin resistance appeared to mediate the association between PCOS and coronary artery calcification, independently of obesity.[51]


An unfavorable lipid profile characterized by a low HDL level can occur in HIV positive patients. The lipid profile may further deteriorate after receiving protease inhibitor based treatment, leading to increased CAD risk.[52]

CAD and GH Deficiency

According to a study conducted on 665 adults with growth hormone deficiency, increased total and LDL cholesterol or low HDL cholesterol were reported in 22 to 45% of patients prior to their treatment.[53] More recently, increased mortality from cardiovascular causes was described in a large prospective trial involving 1014 hypopituitaric patients in the United Kingdom.[54] Hence, it can be hypothesized that low HDL can possibly be associated with higher risk of CAD particularly in growth hormone deficient patients.

CAD in Rheumatoid arthritis

Lipids in general, received only modest attention in the prognosis of CAD in rheumatoid arthritis all these days. With the exception of a single study,[55] most investigators agreed that total, LDL and HDL cholesterol and triglycerides are reduced in active rheumatoid arthritis compared to inactive disease, non-inflammatory arthritis or normal controls,[56] with an inverse correlation between the lipid values and the acute phase response. The low lipid profile may appear to be advantageous, except for the low HDL, which carries an adverse prognostic effect on CAD development and progression in rheumatoid arthritis patients.[23]

Post-CAD Treatment

Residual cardiovascular disease risk, defined as risk of recurrent cardiovascular disease events after management of coronary artery disease, may remain after treatment with statins and it may stem, at least partially, from low HDL cholesterol and/or elevated triglycerides.[57]

CAD in Experimental Models

The association between low HDL level and CAD prognosis can further be understood from experimental models. Both atherosclerotic lesion prevention and low HDL level associated preexisting atherosclerotic lesion regression have been demonstrated in transgenic mice or rabbits following expressions of high levels of human apo A-I,[58][59] by somatic gene transfer of apo A-I,[60] by administration of oral apo A-1 mimetic peptides[61] or by administration of apo A-I Milano, which is a natural variant of apo A-I.[62] Furthermore, liver-directed gene transfer of human apo A-I results in significant regression of pre-existing atherosclerosis after four weeks.[63]

Atrial Fibrillation

Four and a half years follow-up of 4544 individuals who met the criteria for metabolic syndrome approved by the American Heart Association and the National Heart, Lung, and Blood Institute, revealed that 265 patients developed atrial fibrillation. The risk of developing atrial fibrillation was significantly greater in those individuals with metabolic syndrome. In the absence of elevated triglycerides, the risk of developing atrial fibrillation was found to be higher among patients with low HDL cholesterol, hypertension, obesity, and impaired glucose tolerance.[64]

Congestive Heart Failure

A prospective evaluation of the prognostic relationship of HDL levels in patients with severe heart failure was conducted by examining 132 consecutive patients. This study revealed that lower HDL levels correlate with worse prognosis and higher mortality independently of the etiology of the heart failure.[65]

Post Cardiac Procedures

HDL cholesterol is an important predictor of survival in post-CABG patients. In a study involving more than 8500 patients with years of follow-up, HDL cholesterol was found to be the most important metabolic predictor of post-CABG survival. Approximately one third of the patients survived at 15 years when their HDL levels were ≦35 mg/dL at the time of CABG. Therefore, the measurement of HDL cholesterol provides a compelling strategy for the identification of high-risk subsets of patients who undergo CABG.[66]

Low HDL cholesterol is also an independent predictor of the long-term outcome after coronary artery stenting. The combination of low HDL cholesterol and elevated inflammatory markers identified the high-risk patients.[67]

Isolated low serum HDL-cholesterol is also a risk factor for the development of coronary artery disease and may contribute to the development of saphenous venous graft disease.[68]

Chronic Kidney Disease

In a study involving a European population where 176 chronic kidney disease (CKD) patients were followed up for 84 months, low HDL cholesterol levels, diabetes and hypertension were found to be associated with reduced GFR. The HDL cholesterol level was the only lipid parameter that was found to affect the progression of CKD independently of the presence of diabetes. Hence, a low level of plasma HDL cholesterol can be considered as a poor prognostic sign in CKD patients.[69]


High density lipoprotein cholesterol has recently received much attention as a possible risk marker of prostate cancer development and prognosis.[70] In addition, preoperative low serum HDL cholesterol concentration or high TC/HDL cholesterol ratio might be a potential biomarker of advanced pN(2-3) stages in gastric cancer patients, especially those with the histologically differentiated type.[71] Preoperative serum HDL-cholesterol levels retrospectively examined in 184 patients who had undergone gastrectomy revealed a positive correlation between low preoperative serum HDL-cholesterol levels and prognosis for gastric cancer.[72] A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it can be hypothesized that the low HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in proliferating tissues.[73]


A Model for End-Stage Liver Disease (MELD) score ≥18 and TC ≤2.8 mmol/L are two important indexes to predict the prognosis of patients with decompensated cirrhosis. The serum triglycerides, total cholesterol, HDL and LDL levels were lowered with the increase of the MELD score. Their combination can effectively predict the long-term prognosis of patients with decompensated cirrhosis.[74] In an Asian study, an inverse correlation of serum levels of HDL and APO A-I with the liver reserve and disease severity in cirrhotic patients with severe sepsis was found. Low level of HDL and APO A-I were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.[75] In another study, HDL cholesterol in noncholestatic cirrhotic patients was found to be a liver function test as well as an indicator of prognosis.[76]


A study involving academic nursing home patients revealed that the prevalence of increased serum LDL cholesterol and decreased serum HDL cholesterol were found to be significantly higher in elderly patients with atherosclerotic vascular disease plus dementia (72%) and also in dementia without atherosclerotic vascular disease (68%) than in patients with no dementia or atherosclerotic vascular disease.[42] These results suggest a possible prognostic role of HDL levels in dementia with or without atherosclerotic vascular disease.

Kawasaki Disease

Children with Kawasaki disease are more likely to have low HDL than the general pediatric population. This finding suggests a possible association between low HDL levels and the vascular complications of Kawasaki disease.[77]

Nonalcoholic Fatty Liver Disease

The negative association between HDL-cholesterol and liver-fat content is a known phenomenon. Thus the prognosis of NAFLD, which is one of the commonest causes of chronic liver disease both in US and worldwide, is worsened by low HDL levels.[78][79]


Low HDL level was found to be independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlated with increased platelet activation.[80] Another study found that serum levels of HDL and apo-AI are inversely correlated with liver reserve and disease severity in cirrhotic patients with severe sepsis. Both were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.[75] A low HDL cholesterol level on day one of severe sepsis has been shown to be significantly associated with an increase in mortality and adverse clinical outcomes.[81]

Acute Ischemic Stroke

Low HDL has been established as one of the risk factors for acute ischemic stroke. Patients with acute ischemic stroke were found to have a significantly smaller HDL size, with more HDL3a, HDL3b and HDL3c and less HDL2b subclasses. Large artery atherosclerotic stroke and lacunar ischemic stroke had the strongest association with high total cholesterol levels and low HDL cholesterol levels in a case-control study.[82]


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