Change in high-density lipoprotein cholesterol and risk of subsequent hospitalization for coronary artery disease or stroke among patients with type 2 diabetes mellitus

The association between the changes in high-density lipoprotein (HDL) cholesterol and the risk of cardiovascular (CVD) or cerebrovascular hospitalization among patients with type 2 diabetes remains unclear. We conducted a retrospective observational cohort study of 30,067 members of the Kaiser Permanente Northwest and Georgia regions, who had type 2 diabetes and 2 HDL cholesterol measurements 6 to 24 months apart in 2001 to 2006. We followed up the cohort for ≤8 years (through 2009) to determine whether the change in HDL cholesterol was associated with subsequent CVD hospitalization. We examined the HDL cholesterol change continuously and by 3 categories: HDL cholesterol increased ≥6.5 mg/dl, decreased ≥6.5 mg/dl, or remained within ±6.4 mg/dl. The Cox regression models were adjusted for the baseline HDL cholesterol and demographic and clinical risk factors. During a mean follow-up of 55.8 ± 23.8 months, 3,023 patients (10.1%) experienced a CVD hospitalization. After multivariate adjustment, each 5 mg/dl of baseline HDL cholesterol was significantly associated with a 6% lower CVD hospitalization risk (hazard ratio 0.94 per 5 mg/dl, 95% confidence interval 0.92 to 0.95, p <0.0001) and each 5-mg/dl increase in HDL cholesterol was associated with a 4% CVD risk reduction (hazard ratio 0.96, 95% confidence interval 0.94 to 0.99, p <0.003). In the categorical analysis, a ≥6.5-mg/dl HDL cholesterol decrease was associated with an 11% increased CVD risk (hazard ratio 1.11, 95% confidence interval 1.00 to 1.24, p = 0.047) and a ≥6.5-mg/dl increase was associated with an 8% CVD risk reduction (hazard ratio 0.92, 95% confidence interval 0.84 to 1.01, p = 0.077) relative to those with stable HDL cholesterol. In conclusion, our results add to the growing body of evidence that increasing the HDL cholesterol levels might be an important strategy for CVD risk reduction. The prevention of HDL cholesterol decreases could be equally important.     

Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease

BACKGROUND: Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline. METHODS AND RESULTS: We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of baseline RDW and further adjustment for hematocrit and other cardiovascular risk factors, a graded independent relation between RDW and death was observed (P for trend=0.001). For instance, participants with RDW in the highest quartile had an adjusted hazard ratio for death of 1.78 (95% confidence interval, 1.28 to 2.47) compared with those in the lowest quartile. Higher levels of RDW were also associated with increased risk of coronary death/nonfatal myocardial infarction, new symptomatic heart failure, and stroke. CONCLUSIONS: We found a graded independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infarction but no symptomatic heart failure at baseline.     

Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6+/-1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 micromol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.     

Relation of plasma lipoprotein levels with low-grade inflammation in white men without clinical evidence of myocardial ischemia

There is a growing body of evidence indicating that high triglyceride levels are an independent risk factor for cardiovascular disease (CVD) events. In this study we compared the association of fasting levels of non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, and triglycerides with white blood cell (WBC) count, an inflammatory marker associated with an adverse CVD prognosis. We studied 458 asymptomatic men (46.0 +/- 7.0 years old) who presented for CVD risk stratification. WBC count (x10(9) cells/L) increased significantly across increasing tertiles of triglyceride level (tertile 1, 6.04 +/- 1.49; tertile 2 6.21 +/- 1.44; tertile 3 6.78 +/- 1.73, p <0.0001), whereas a trend of lower WBC counts was observed across increasing tertiles of HDL cholesterol (tertile 1, 6.52 +/- 1.62; tertile 2, 6.24 +/- 1.50; tertile 3, 6.21 +/- 1.61, p = 0.08). In models adjusted for age, gender, and CVD risk factor, the odds ratio for a high WBC count (quartile > or =4 vs lower 3 quartiles) was significantly higher with increasing levels of triglyceride (2.4, 95% confidence interval 1.3 to 4.8, p = 0.02). When all lipid variables were introduced in the models in addition to traditional CVD risk factors, the association between plasma triglyceride level and WBC count persisted (p = 0.04), which was not found for other lipid parameters. In conclusion, in our study, only plasma triglyceride level was independently associated with a higher WBC count.     

Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis

ObjectivesPsoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis.Methods and resultsWe prospectively enrolled a consecutive sample of patients with psoriasis (n = 122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n = 134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n = 100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dl (36–58) vs 50 (42–62), p < 0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002–1498) vs 1115 (935–1291), p = 0.02] with decrease in LDL size [20.6 (20.3–21.1) vs 21.3 (20.6–21.1), p < 0.001] beyond CV risk factors and HOMA-IR (p = 0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta ?0.14, p = 0.001).ConclusionsThese data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.     

Serum phospholipid transfer protein mass as a possible protective factor for coronary heart diseases.

BACKGROUND: Phospholipid transfer protein (PLTP) can generate pre-beta high-density lipoprotein (HDL), an efficient acceptor of peripheral cholesterol, by mediating a process called HDL conversion. The transfer of phospholipids to immature HDL is also essential in maintaining reverse cholesterol transport. The phospholipid transfer activity of PLTP has been associated with various patho-physiological conditions; however, little information is available concerning the relationship between PLTP mass and disease. METHODS AND RESULTS: Using a sandwich enzyme-linked immunosorbent assay, PLTP concentration was measured and related to the risk of developing cardiovascular disease in a worksite-based cohort of Japanese men (n=2,567). Multiple linear regression analysis showed significant associations between PLTP and HDL cholesterol, triglycerides, low-density lipoprotein cholesterol, and body mass index (standardized beta=0.395, -0.191, -0.064, and -0.064, respectively; R(2)=0.31). During the follow-up period, there were 10 cases of coronary heart disease (CHD) and 7 of stroke. The multivariate adjusted relative risk of CHD was 0.46 (95% confidence interval, 0.20-1.07) for an increase of 1 standard deviation in the PLTP value (p=0.071). PLTP concentration was not related to the risk of stroke. CONCLUSIONS: The results of this prospective study indicate that the serum PLTP concentration would serve as a predictor of CHD, independent of HDL cholesterol, triglycerides and other established risk factors.     

Role of non-high-density lipoprotein cholesterol in predicting cerebrovascular events in patients following myocardial infarction

Although there appears to be a role for statins in reducing cerebrovascular events, the exact role of different lipid fractions in the etiopathogenesis of cerebrovascular disease (CVD) is not well understood. A secondary analysis of data collected for the placebo arm (n = 2,078) of the Cholesterol and Recurrent Events (CARE) trial was performed. The CARE trial was a placebo-controlled trial aimed at testing the effect of pravastatin on patients after myocardial infarction. Patients with histories of CVD were excluded from the study. A Cox proportional-hazards model was used to evaluate the association between plausible risk factors (including lipid fractions) and risk for first incident CVD in patients after myocardial infarction. At the end of 5 years, 123 patients (6%) had incident CVD after myocardial infarction (76 with stroke and 47 with transient ischemic attack). Baseline non-high-density lipoprotein (HDL) cholesterol level emerged as the only significant lipid risk factor that predicted CVD; low-density lipoprotein cholesterol and HDL cholesterol were not significant. The adjusted hazard ratios (adjusted for age, gender, hypertension, diabetes mellitus, and smoking) for CVD were 1.28 (95% confidence interval [CI] 1.06 to 1.53) for non-HDL cholesterol, 1.14 (95% CI 0.96 to 1.37) for low-density lipoprotein cholesterol, and 0.90 (95% CI 0.75 to 1.09) for HDL cholesterol (per unit SD change of lipid fractions). This relation held true regardless of the level of triglycerides. After adjustment for age and gender, the hazard ratio for the highest natural quartile of non-HDL was 1.76 (95% CI 1.05 to 2.54), compared to 1.36 (95% CI 0.89 to 1.90) for low-density lipoprotein cholesterol. In conclusion, non-HDL cholesterol is the strongest predictor among the lipid risk factors of incident CVD in patients with established coronary heart disease.     

Should pulse pressure become part of the Framingham risk score?

An increased pulse pressure suggests aortic stiffening. New evidence also suggests that pulse pressure is a more sensitive measure of risk than other indexes of blood pressure in middle-aged and older persons. The objective of the study was to relate pulse pressure to the risk of cardiovascular events in the general population, and to assess whether pulse pressure could improve the Framingham risk prediction. A total of 378 men and 391 women over the age of 50 years (mean 62.7 years) were followed. Sex-specific Framingham cardiovascular risk scores were derived from age, systolic pressure, diastolic pressure, total and HDL cholesterol, smoking status and the presence or absence of diabetes mellitus. The cutoff points used to develop a pulse pressure score were calculated by determining the percentile points corresponding to the blood pressure categories in the Framingham risk score. We calculated relative hazard rates by multiple Cox regression. After a median follow-up of 7.2 years (range: 11 months-15 years), a total of 148 cardiovascular events occurred. In Cox regression analysis, a 10 mmHg higher pulse pressure was associated with 31% (P<0.0001) increase in the risk for cardiovascular events (fatal and nonfatal) after adjustment for sex, age, total and HDL cholesterol, smoking and the presence of diabetes mellitus. After adjustment for the aforementioned risk factors, a one-point increment in the blood pressure and pulse pressure scores was associated with a 40 and 48% (both P<0.0001) increase in the risk of fatal and nonfatal cardiovascular events, respectively. When both the blood pressure and pulse pressure scores were forced into a Cox model, only the pulse pressure score remained statistically significant (P<0.0001) with a relative hazard rate of 1.37 (CI: 1.16-1.69). These prospective data suggest that pulse pressure may improve the Framingham risk prediction among middle-aged and older individuals. Further studies, especially in the Framingham cohort, are warranted.     

Microalbuminuria in Type 2 diabetes: an independent predictor of cardiovascular mortality

Background: Microalbuminuria has been shown to be associated with cardiovascular mortality in type 2 diabetic subjects. It is unclear to what extent this is due to the increased prevalence of other cardiac risk factors. Aims: To examine the relationship of urine albumin excretion to cardiovascular mortality and to determine its status as an independent risk factor. Methods: In a prospective longitudinal study from 1986–1999 we followed 666 type 2 diabetic subjects from a diabetes outpatient service. Cardiovascular risk factors including urine albumin concentration were measured at study entry. Cox proportional hazards regression was used to determine risk factors for mortality. The hazard ratios of microalbuminuria and macroalbuminuria for all cause, cardiovascular and coronary heart disease mortality were determined after accounting for other cardiac risk factors including blood pressure, glycated haemoglobin, total cholesterol, HDL cholesterol, triglycerides, urea, smoking, body mass index, patient age and disease duration. Results: The prevalence of urine albumin of 30–300 mg/L at study entry was 31.7%. A total of 167 deaths occurred (80 from cardiovascular disease). Mortality hazard ratios in subjects with urine albumin of 30–300 mg/L as compared to <30 mg/L, adjusted for age, sex and other cardiovascular risk factors were 1.77 (95% CI 1.22–2.57, p=0.002) for all causes, 2.34 (95% CI 1.38–3.99, p=0.002) for cardiovascular and 1.78 (95% CI 0.97–3.26, p=0.061) for coronary heart disease (CHD) mortality. Other factors significantly associated with cardiovascular mortality included diastolic blood pressure, HDL cholesterol and glycated haemoglobin. Total cholesterol and log triglyceride were significantly associated with CHD mortality. Disease duration, age at diagnosis, smoking and body mass index were not related to cardiovascular or CHD mortality. Conclusions: We confirm microalbuminuria as an independent predictor of mortality in type 2 diabetes despite its association with a number of conventional cardiovascular risk factors.     

High-density lipoprotein: Antioxidant and anti-inflammatory properties

The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is an important component of its ability to protect against cardiovascular disease. In addition, the anti-inflammatory properties of HDL are important as well. As part of the innate immune system, HDL appears to have evolved to increase inflammation in the presence of an acute phase response but to inhibit inflammation in the absence of an acute phase response. In a study of humans with coronary heart disease, it was found that the patients who had proinflammatory HDL prior to statin therapy (and half of them despite a profound decrease in plasma lipids following statin therapy) continued to have proinflammatory HDL. Anti-inflammatory HDL was effective in promoting cholesterol efflux whereas proinflammatory HDL was relatively weak in its ability to promote cholesterol efflux. Oxidative alterations of the main protein of HDL, apolipoprotein A-I, impaired its capacity to promote cholesterol efflux from monocyte macrophages. Therefore, HDL composition, structure, and function appear to be more crucial than HDL cholesterol concentrations in determining risk for cardiovascular disorders.     

Prognostic usefulness of free fatty acids in patients with stable coronary heart disease

Circulating nonesterified or free fatty acids (FFAs) may contribute to the development of cardiovascular pathology and correlate with ischemia in acute cardiovascular conditions. The aim of this study was to assess whether serum levels of FFAs are associated with long-term prognosis in subjects with stable coronary heart disease. This observational prospective cohort study included 1,206 participants in 3-weeks inpatient rehabilitation programs after acute myocardial infarction, coronary syndromes, or coronary intervention at 2 rehabilitation clinics in Germany (1999 to 2000). Eight-year prognosis (time to a secondary fatal or nonfatal cardiovascular disease event including myocardial infarction and stroke [n = 153] and time to death from any cause [n = 124]) was examined according to FFA quartiles and in spline regression. FFAs were correlated with established serum markers of cardiovascular risk and strongly related to secondary cardiovascular events and all-cause mortality in age- and gender-adjusted analysis. When additionally controlling for multiple established risk factors and risk markers, the hazard ratio in the fourth versus first quartile was 1.34 (95% confidence interval 0.79 to 2.24) for secondary cardiovascular events and 1.09 (95% confidence interval 0.62 to 1.91) for all-cause mortality. Dose-response modeling suggested that very high FFAs might predict an increased risk for mortality (hazard ratio 1.98, 95% confidence interval 0.98 to 4.02, for 95th percentile vs first quartile). In conclusion, FFAs are closely correlated with cardiovascular risk markers, and in particular, very high FFA might identify patients with stable coronary heart disease with worse prognoses.     

Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Münster Study.

The incidence of atherosclerotic coronary artery disease (CAD) was assessed in 4,576 male participants of the Prospective Cardiovascular Münster (PROCAM) study, aged 40-64 years, over a 4-year follow-up period. In this time, 122 study participants developed atherosclerotic CAD (89 definite nonfatal myocardial infarctions and 33 definite atherosclerotic CAD deaths). Univariate analysis revealed a significant association between the incidence of atherosclerotic CAD, and high-density lipoprotein (HDL) cholesterol (p < 0.001) and triglyceride (p < 0.01) levels. The relation to HDL cholesterol remained after adjustment for other risk factors. By contrast, the relation between the incidence of atherosclerotic CAD and triglycerides disappeared if, in a multivariate analysis by means of a multiple logistic function, cholesterol or HDL cholesterol was taken into account. However, the data suggested that hypertriglyceridemia is a powerful additional coronary risk factor, when excessive triglycerides coincide with a high ratio (> 5.0) of plasma low-density lipoprotein (LDL) cholesterol to HDL cholesterol. Even though the prevalence of this subgroup was only 3.7%, it included a quarter of all atherosclerotic CAD events observed.     

High-Density Lipoprotein Functionality in Coronary Artery Disease

The role of high-density lipoprotein (HDL) in cardiovascular atheroprotection is well established. Epidemiological data have clearly demonstrated an inverse relationship between HDL levels and the risk for coronary artery disease, which is independent of the low-density lipoprotein levels. However, more recent data provide evidence that high HDL levels are not always protective and that under certain conditions may even confer an increased risk. Thus, a new concept has arisen, which stresses the importance of HDL functionality, rather than HDL concentration per se, in the assessment of cardiovascular risk. HDL functionality is genetically defined but can also be modified by several environmental and lifestyle factors, such as diet, smoking or certain pharmacologic interventions. Furthermore, HDL is consisted of a heterogeneous group of particles with major differences in their structural, biological and functional properties. Recently, the cholesterol efflux capacity from macrophages was proven to be an excellent metric of HDL functionality, because it was shown to have a strong inverse relationship with the risk of angiographically documented coronary artery disease, independent of the HDL and apolipoprotein A-1 levels, although it may not actually predict the prospective risk for cardiovascular events. Thus, improving the quality of HDL may represent a better therapeutic target than simply raising the HDL level, and assessment of HDL function may prove informative in refining our understanding of HDL-mediated atheroprotection.     

Radical-trapping activity,blood pressure,and carotid enlargement in women

The aim of this study was to evaluate the influence of traditional and nontraditional (oxidation markers) cardiovascular risk factors on the degree of adaptive response of the carotid wall to atherosclerotic disease, a process known as arterial enlargement. Five thousand sixty-two clinically healthy, middle-aged women living in the area of Naples participated in the "Progetto Atena" study; 310 of these women (potentially at higher atherosclerotic risk) underwent a high-resolution ultrasound scan of the carotid arteries. In addition to routine biochemical tests, these women had the determination of serum IgG antibody titer against oxidized LDL and measurement of thiobarbituric acid reactive substances and total radical-trapping activity potential of plasma. Age, systolic blood pressure, body mass index, and radical-trapping activity were all positively correlated with external and internal common carotid diameters, whereas triglycerides (positively) and HDL cholesterol (inversely) were related only to external diameter. After controlling for traditional cardiovascular risk factors, associations still persisted for age, systolic blood pressure, and plasma radical-trapping activity with external carotid diameters. However, in the quartile of women with highest total cholesterol (>7.38 mmol/L), the slope of the regression line between systolic blood pressure and external diameter was significantly flatter than in the three other quartiles (test for difference, P=0.014). Outward carotid enlargement is related to traditional and nontraditional risk factors and comes even before plaque development. Women with poor resistance to oxidative stress potentially have a difficulty to remodel their arteries in response to atherosclerotic stimuli.     

Apolipoprotein B/A-I and total cholesterol/high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein

Kappelle PJWH, Gansevoort RT, Hillege JL, Wolffenbuttel BHR, Dullaart RPF on behalf of the PREVEND study group (University Medical Center Groningen and University of Groningen, Groningen, The Netherlands). Apolipoprotein B/A‐I and total cholesterol/high‐density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C‐reactive protein. J Intern Med 2011; 269 : 232–242. Abstract. Background. The total cholesterol/high‐density lipoprotein cholesterol (TC/HDL‐C) and apolipoprotein (apo) B/A‐I ratios predict major adverse cardiovascular events (MACEs). The extent to which these associations are modified by high‐sensitivity C‐reactive protein (hs‐CRP) and albuminuria is largely unknown. We compared the strength of these ratios with first MACE in the general population and determined whether these associations remain when taking account of these risk markers. Subjects and methods. A prospective case–cohort study was performed among 6948 subjects (PREVEND cohort) without previous cardiovascular disease and who did not use lipid‐lowering drugs initially. Fasting serum TC, low‐density lipoprotein cholesterol (LDL‐C), HDL‐C, non‐HDL‐C, apoB, apoA‐I, triglycerides, hs‐CRP and albuminuria were measured at baseline. The composite endpoint was incident MACE. Results. A total of 362 first cardiovascular events occurred during 7.9 years of follow‐up. All pro‐ and anti‐atherogenic measures of lipoproteins and apos predicted MACEs in age‐ and sex‐adjusted Cox proportional hazard analyses (P = 0.018 to P < 0.001). The age‐ and sex‐adjusted hazard ratio (HR) was 1.37 [95% confidence interval (CI), 1.26–1.48] for the apoB/apoA‐I ratio and 1.24 (95% CI, 1.18–1.29) for the TC/HDL‐C ratio (both P < 0.001). These relationships were essentially unaltered after additional adjustment for triglyceride levels. Pair‐wise comparison revealed that these ratios were of similar importance in age‐ and sex‐adjusted analysis (P = 0.397). The HRs of apoB/apoA‐I (P < 0.001) and TC/HDL‐C (P < 0.001) for risk of MACEs were only marginally attenuated by additional controlling for traditional risk factors (hypertension, diabetes, obesity and smoking), hs‐CRP and albuminuria. Conclusions. First MACE is associated with both the fasting serum apoB/apoA‐I ratio and the TC/HDL‐C ratio in the general population, independently of triglycerides, hs‐CRP and albuminuria.     

Serum lipids and lipoproteins after myocardial infarction: associations with cardiovascular mortality and experience in the Aspirin Myocardial Infarction Study

Serum cholesterol and triglyceride levels were measured at baseline in 4021 men and 503 women (myocardial infarction survivors) participating in the Aspirin Myocardial Infarction Study (AMIS). A cohort of participants (1824 men and 226 women) had, in addition, a determination of high-density lipoprotein (HDL) cholesterol and an estimate of low-density lipoprotein (LDL) cholesterol. In comparison with values obtained for normal Americans by the Lipid Research Clinics Prevalence Study Group, AMIS participants had higher serum cholesterol, higher serum triglyceride, higher LDL cholesterol, and lower HDL cholesterol levels. These values were the most disparate in the women and younger men. The serum total cholesterol, the ratio of LDL to HDL cholesterol, and the serum triglyceride level were significantly related (p less than 0.05) to the 3-year cardiovascular mortality rate for men less than 55 years of age (univariate relationships). For men older than 55 years, these relationships were not statistically significant. After adjustment for multiple risk factors, serum cholesterol and the ratio of LDL to HDL cholesterol remained significant risk factors for cardiovascular death and the combined incidence of cardiovascular death or nonfatal myocardial infarction in men less than age 55 years.     

ATP-binding cassette A1 protein and HDL homeostasis

For three decades, low-density lipoprotein (LDL) dominated research into cholesterol metabolism and atherosclerosis, whereas scant attention was paid to high-density lipoprotein (HDL), an equally important risk factor for cardiovascular disease. This low interest reflected the lack of knowledge about physiological HDL receptors. As a result, our understanding of HDL-cell interactions failed to develop alongside that of LDL, and mechanisms through which atheroprotective HDL promoted clearance of cholesterol from peripheral cells remained poorly-defined. Interest was kindled with the recognition that scavenger receptor class B, type I is the cell-surface protein in hepatocytes and steroidogenic tissues which selectively extracts cholesteryl esters from HDL. Greater impetus still was given by the discovery that mutations in the gene encoding the ATP-binding cassette transporter, class A1 (ABCA1) are the cause of Tangier disease, a rare recessive disorder with near-absent plasma HDL. The ABCA1 transmembrane protein is crucial for efficient efflux of cellular cholesterol and HDL maturation and has emerged as a promising therapeutic target for cardiovascular disease. The hope is that new drugs, regulating ABCA1 activity and HDL homeostasis, will accelerate cholesterol efflux from lipid-laden foam cells and thus promote regression of atherosclerotic lesions.     

Day-night dip and early-morning surge in blood pressure in hypertension: prognostic implications

We investigated the relationship between the day-night blood pressure (BP) dip and the early morning BP surge in an cohort of 3012 initially untreated subjects with essential hypertension. The day-night reduction in systolic BP showed a direct association with the sleep trough (r = 0.564; P < 0.0001) and the preawakening (r = 0.554; P < 0.0001) systolic BP surge. Over a mean follow-up period of 8.44 years, 268 subjects developed a major cardiovascular event (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and heart failure requiring hospitalization) and 220 subjects died. In a Cox model, after adjustment for predictive covariates, including age, sex, diabetes mellitus, cigarette smoking, total cholesterol, left ventricular hypertrophy on ECG, estimated glomerular filtration rate, and average 24-hour systolic BP, a blunted sleep trough (≤ 19.5 mm Hg; quartile 1) and preawakening (≤ 9.5 mm Hg; quartile 1) BP surge was associated with an excess risk of events (hazard ratio, 1.66 [95% CI, 1.14-2.42]; P = 0.009; hazard ratio, 1.71 [95% CI, 1.12-2.71]; P = 0.013). After adjustment for the same covariates, neither the dipping pattern nor the measures of early morning BP surge were independent predictors of mortality. In conclusion, in initially untreated subjects with hypertension, a blunted day-night BP dip was associated with a blunted morning BP surge and vice versa. In these subjects, a blunted morning BP surge was an independent predictor of cardiovascular events, whereas an excessive BP surge did not portend an increased risk of events.     

ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins

The mechanisms responsible for the inverse relationship between plasma high-density lipoprotein (HDL) levels and atherosclerotic cardiovascular disease are poorly understood. The ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to lipid-poor apolipoproteins but not to HDL particles that constitute the bulk of plasma HDL. We show that two ABC transporters of unknown function, ABCG1 and ABCG4, mediate isotopic and net mass efflux of cellular cholesterol to HDL. In transfected 293 cells, ABCG1 and ABCG4 stimulate cholesterol efflux to both smaller (HDL-3) and larger (HDL-2) subclasses but not to lipid-poor apoA-I. Treatment of macrophages with an liver X receptor activator results in up-regulation of ABCG1 and increases cholesterol efflux to HDL. RNA interference reduced the expression of ABCG1 in liver X receptor-activated macrophages and caused a parallel decrease in cholesterol efflux to HDL. These studies indicate that ABCG1 and ABCG4 promote cholesterol efflux from cells to HDL. ABCG1 is highly expressed in macrophages and probably mediates cholesterol efflux from macrophage foam cells to the major HDL fractions, providing a mechanism to explain the relationship between HDL levels and atherosclerosis risk.