Blood lipids and women heart health

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Hi All,

The below appears to express, albeit only in women, the risks of various blood

lipid

measures that we monitor to ensure our beneficial effects from CR.

It being a prospective study seems to lend weight to the findings. Specific

ratios

are important.

It seemed to total cholesterol was a fairly good marker, and additional HDL to

determined the total cholesterol/HDL ratio is much better than determining

additional LDL blood levels.

The pdf is available.

This Week in JAMA

JAMA. 2005;294:281.

.... Measuring CVD Risk in Women

A variety of lipid biomarkers and their ratios are recommended for predicting

risk

of future cardiovascular disease (CVD) events, but their clinical utility has

not

been directly compared. In a cohort of women participants in a clinical trial

with

10 years of follow-up for first cardiovascular event, Ridker and colleagues (SEE

ARTICLE) evaluated baseline levels of total cholesterol, low-density lipoprotein

cholesterol, high-density lipoprotein cholesterol (HDL-C), non–HDL-C,

apolipoproteins A-I and B100, high-sensitivity C-reactive protein, and several

ratios of these measurements as predictors of future CVD events. They found that

non–HDL-C and the ratio of total cholesterol to HDL-C were as good or better

than

apolipoprotein fractions to predict future CVD events. ...

Non–HDL Cholesterol, Apolipoproteins A-I and B100, Standard Lipid Measures,

Lipid

Ratios, and CRP as Risk Factors for Cardiovascular Disease in Women

M Ridker, MD; Nader Rifai, PhD; R. Cook, ScD; Bradwin, BS;

E.

Buring, ScD

JAMA. 2005;294:326-333.

Context Current guidelines for cardiovascular risk detection are controversial

with

regard to the clinical utility of different lipid measures, non–high-density

lipoprotein cholesterol (non–HDL-C), lipid ratios, apolipoproteins, and

C-reactive

protein (CRP).

Objective To directly compare the clinical utility of total cholesterol,

low-density lipoprotein cholesterol (LDL-C), HDL-C, non–HDL-C, apolipoproteins

A-I

and B100, high-sensitivity CRP, and the ratios of total cholesterol to HDL-C,

LDL-C

to HDL-C, apolipoprotein B100 to apolipoprotein A-I, and apolipoprotein B100 to

HDL-C as predictors of future cardiovascular events in women.

Design, Setting, and Participants Prospective cohort study of 15 632 initially

healthy US women aged 45 years or older (interquartile range, 48-59 years) who

were

enrolled between November 1992 and July 1995. All participants were followed up

over

a 10-year period for the occurrence of future cardiovascular events.

Main Outcome Measure Hazard ratios (HRs) and 95% confidence intervals (CIs) for

first-ever major cardiovascular events (N = 464) according to baseline levels of

each biomarker.

Results After adjustment for age, smoking status, blood pressure, diabetes, and

body mass index, the HRs for future cardiovascular events for those in the

extreme

quintiles were 1.62 (95% CI, 1.17-2.25) for LDL-C, 1.75 (95% CI, 1.30-2.38) for

apolipoprotein A-I, 2.08 (95% CI, 1.45-2.97) for total cholesterol, 2.32 (95%

CI,

1.64-3.33) for HDL-C, 2.50 (95% CI, 1.68-3.72) for apolipoprotein B100, 2.51

(95%

CI, 1.69-3.72) for non–HDL-C, and 2.98 (95% CI, 1.90-4.67) for high-sensitivity

CRP

(P<.001 for trend across all quintiles). The HRs for the lipid ratios were 3.01

(95%

CI, 2.01-4.50) for apolipoprotein B100 to apolipoprotein A-I, 3.18 (95% CI,

2.12-4.75) for LDL-C to HDL-C, 3.56 (95% CI, 2.31-5.47) for apolipoprotein B100

to

HDL-C, and 3.81 (95% CI, 2.47-5.86) for the total cholesterol to HDL-C (P<.001

for

trend across all quintiles). The correlation coefficients between

high-sensitivity

CRP and the lipid parameters ranged from –0.33 to 0.15, and the clinical cut

points

for CRP of less than 1, 1 to 3, and higher than 3 mg/L provided prognostic

information on risk across increasing levels of each lipid measure and lipid

ratio.

Conclusions Non–HDL-C and the ratio of total cholesterol to HDL-C were as good

as

or better than apolipoprotein fractions in the prediction of future

cardiovascular

events. After adjustment for age, blood pressure, smoking, diabetes, and

obesity,

high-sensitivity CRP added prognostic information beyond that conveyed by all

lipid

measures.

.... RESULTS

Mean (SD) age at baseline for the 15 632 initially healthy women followed up in

this

study was 54.4 (7.6) years (interquartile range, 48-59 years) and the mean (SD)

body

mass index was 26.3 (5.3). A total of 1910 women (12%) were current smokers, 527

(3%) had diabetes, 3847 (25%) had a history of hypertension, and 1819 (13%) had

a

family history of myocardial infarction in a parent before age 60 years.

Baseline distributions of each lipid variable as well as that of

high-sensitivity

CRP are provided in Table 1. Values are similar to those anticipated in

populations

of healthy middle-aged women not taking hormone therapy.

Table 2 presents the Spearman correlation coefficients between each lipid

parameter.

As expected, strong correlations were observed between LDL-C and apolipoprotein

B100

(r = 0.81), between LDL-C and non–HDL-C (r = 0.92), between LDL-C and total

cholesterol (r = 0.91), between HDL-C and apolipoprotein A-I (r = 0.80), between

total cholesterol and non–HDL-C (r = 0.94), and most importantly between

non–HDL-C

and apolipoprotein B100 (r = 0.87). The correlation coefficients between

high-sensitivity CRP and the measured lipid parameters were r = 0.17 for total

cholesterol, r = 0.15 for LDL-C, r = –0.33 for HDL-C, r = 0.27 for non–HDL-C, r

=

–0.19 for apolipoprotein A-I, and r = 0.29 for apolipoprotein B100.

Over an average of 10 years of follow-up, rates of completed follow-up for the

WHS

exceeded 97% for morbidity and 99% for mortality. During this period, 464

participants developed a first-ever confirmed cardiovascular end point (131

myocardial infarction, 122 ischemic stroke, 274 coronary revascularization, and

76

cardiovascular death, with many women having 2 of these end points). To avoid

double

counting, only the first event for the participant was used in these analyses.

The HRs for developing future cardiovascular events according to increasing

quintiles of each lipid variable and high-sensitivity CRP are shown in Table 3.

After adjustment for age (years), blood pressure (Framingham categories), body

mass

index, diabetes, and current smoking status, each of the measured parameters was

strongly associated with risk of future cardiovascular events (P<.001 for trend

across all quintiles). The assumption of the proportional hazards model was

valid in

our study in that for each biomarker, the interaction of the HR with 1n (time)

was

not significant (P>.05).

Table 3. Future Cardiovascular Events Among Initially Healthy Women According to

Baseline Lipid Levels, High-Sensitivity C-Reactive Protein, and Calculated Lipid

Ratios *

.............................

-----Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5

............................

Individual Variables

Cholesterol

Total

Median (range), mg/dL 161 (<176) 187 (176-197) 207 (198-216) 228 (217-242) 264

(>242)

No. of events 41 67 79 118 159

RR (95% CI) 1.00 1.40 (0.94-2.08) 1.39 (0.94-2.05) 1.71 (1.19-2.48) 2.08

(1.45-2.97)

LDL

Median (range), mg/dL 85 (<97.7) 107 (97.7-115.4) 124 (115.5-132.1) 142

(132.2-153.9) 171 (>153.9)

No. of events 54 66 74 114 156

RR (95% CI) 1.00 1.06 (0.73-1.54) 1.03 (0.71-1.49) 1.32 (0.94-1.85) 1.62

(1.17-2.25)

HDL

Median (range), mg/dL 35 (<39.5) 43 (39.5-45.9) 49 (46.0-52.6) 57 (52.7-61.5) 69

(>61.5)

No. of events 171 115 66 63 49

RR (95% CI) 1.00 0.84 (0.66-1.07) 0.53 (0.39-0.71) 0.54 (0.39-0.73) 0.43

(0.30-0.61)

Non–HDL

Median (range), mg/dL 109 (<123.2) 135 (123.2-144.9) 155 (145.0-165.5) 177

(165.6-191.0) 213 (>191.0)

No. of events 32 46 85 116 185

RR (95% CI) 1.00 1.15 (0.73-1.82) 1.62 (1.06-2.48) 1.88 (1.25-2.83) 2.51

(1.69-3.72)

Apolipoprotein

A-I

Median (range), mg/dL 116 (<124.1) 130 (124.1-135.4) 141 (135.5-146.2) 152

(146.3-159.8) 171 (>159.8)

No. of events 139 116 71 68 70

RR (95% CI) 1.00 0.91 (0.71-1.17) 0.54 (0.40-0.73) 0.54 (0.40-0.74) 0.57

(0.42-0.77)

B100

Median (range), mg/dL 70 (<79.1) 87 (79.1-93.3) 100 (93.4-108.9) 117

(109.0-126.2)

141 (>126.2)

No. of events 32 52 77 98 205

RR (95% CI) 1.00 1.22 (0.77-1.92) 1.51 (0.98-2.31) 1.53 (1.00-2.32) 2.50

(1.68-3.72)

High-sensitivity CRP

Median (range), mg/L 0.29 (<0.50) 0.75 (0.50-1.08) 1.52 (1.09-2.08) 2.93

(2.09-4.19)

6.62 (>4.19)

No. of events 26 63 79 117 179

RR (95% CI) 1.00 1.85 (1.16-2.96) 1.91 (1.21-3.03) 2.38 (1.52-3.72) 2.98

(1.90-4.67)

Lipid Ratios

Total cholesterol to HDL cholesterol

Median (range) 2.8 (<3.2) 3.5 (3.2-3.8) 4.1 (3.8-4.5) 4.9 (4.5-5.4) 6.2 (>5.4)

No. of events 28 49 64 111 212

RR (95% CI) 1.00 1.63 (1.00-2.64) 1.55 (0.96-2.48) 2.49 (1.59-3.89) 3.81

(2.47-5.86)

LDL cholesterol to HDL cholesterol

Median (range) 1.5 (<1.8) 2.0 (1.8-2.3) 2.5 (2.3-2.8) 3.1 (2.8-3.4) 4.0 (>3.4)

No. of events 32 46 78 107 201

RR (95% CI) 1.00 1.24 (0.78-1.98) 1.74 (1.13-2.69) 1.97 (1.29-3.01) 3.18

(2.12-4.75)

Apolipoprotein B100 to apolipoprotein A-I

Median (range) 0.46 (<0.54) 0.60 (0.54-0.65) 0.71 (0.65-0.78) 0.85 (0.78-0.94)

1.08

(>0.94)

No. of events 31 54 65 114 200

RR (95% CI) 1.00 1.43 (0.91-2.26) 1.45 (0.93-2.25) 1.89 (1.24-2.88) 3.01

(2.01-4.50)

Apolipoprotein B100 to HDL cholesterol

Median (range) 1.1 (<1.4) 1.6 (1.4-1.8) 2.0 (1.8-2.3) 2.6 (2.3-3.0) 3.6 (>3.0)

No. of events 27 54 66 112 205

RR (95% CI) 1.00 1.76 (1.09-2.83) 1.68 (1.05-2.68) 2.35 (1.50-3.67) 3.56

(2.31-5.47)

................................................

Abbreviations: CI, confidence interval; CRP, C-reactive protein; HDL,

high-density

lipoprotein; LDL, low-density lipoprotein; RR, relative risk.

*All analyses adjusted for age in years, blood pressure by Framingham

categories,

body mass index, diabetes, and current smoking status. P<.001 for trend across

all

quintiles.

Of the lipid measures, the strongest association was observed with the highly

intercorrelated variables non–HDL-C and apolipoprotein B100 (Table 3).

Specifically,

the fully adjusted HR for those in the highest compared with lowest baseline

quintile of non–HDL-C was 2.51 (95% CI, 1.69-3.72; LR 2 statistic = 659.6)

whereas

the comparable value for apolipoprotein B100 was 2.50 (95% CI, 1.68-3.72; LR 2

statistic = 660.8). Both non–HDL-C (LR 2 statistic = 642.2) and apolipoprotein

B100

(LR 2 statistic = 636.3) showed stronger association than either total

cholesterol

or LDL-C in these data. By contrast, the magnitude of association for HDL-C

appeared

to be somewhat greater than that of apolipoprotein A-I.

High-sensitivity CRP levels also were associated with future cardiovascular

events

(Table 3); the fully adjusted HR for those in the highest compared with lowest

baseline quintile of high-sensitivity CRP was 2.98 (95% CI, 1.90-4.67; LR 2

statistic = 650.0). The LR 2 statistic for high-sensitivity CRP was greater than

that of total cholesterol and LDL-C but less than that of apolipoprotein B100

and

non–HDL-C, most likely reflecting modest correlations between high-sensitivity

CRP

and some of the nonlipid variables used in the multivariate adjustment. These

direct

comparative HRs and 95% CIs for those in the extreme quintiles of each measured

parameter are presented in Figure 1.

Figure 1. Adjusted Hazard Ratios of Future Cardiovascular Events Among Those in

the

Extreme Quintiles of Each Measured Variable

...............................................

[Arranged in order of increasingly greater hazard ratios at an approximately

linear line of the log of the descending order in the list]

Individual Variables

LDL Cholesterol (LDL-C) [hazard ratio ~1.8]

Apolipoprotein (Apo) A-I

Total Cholesterol [hazard ratio ~2.0]

HDL Cholesterol (HDL-C)

Non–HDL-C

High-Sensitivity CRP

Apo B 100

Apo B 100 to Apo A-I

Lipid Ratios

LDL-C to HDL-C

Apo B 100 to HDL-C

Total Cholesterol to HDL-C [Hazard ratio ~3.3]

..........................................

Hazard ratios (HRs) are adjusted for age (years), blood pressure (Framingham

categories), diabetes, current smoking status, and body mass index. CI indicates

confidence interval; and CRP, C-reactive protein.

Comparative data on risk associated with the ratios of total cholesterol to

HDL-C,

LDL-C to HDL-C, apolipoprotein B100 to apolipoprotein A-I, and apolipoprotein

B100

to HDL-C appear in Table 3. By combining information on 2 components of lipid

risk

into a single clinical variable, all of these lipid ratios provided stronger

evidence of association than that achieved by any of the single variables used

alone. However, despite the apparent superiority of apolipoprotein B100 over

total

cholesterol and LDL-C, the lipid ratio with the strongest association in these

data

was the more traditional ratio of total cholesterol to HDL-C (top vs bottom

quintile

HR, 3.81; 95% CI, 2.47-5.86; P<.001 for trend; LR 2 statistic = 694.3; Table 3).

For

comparison, the relative risk in the top quintile of the ratio of apolipoprotein

B100 to apolipoprotein A-I was 3.01 (95% CI, 2.01-4.50; P<.001 for trend; LR 2

statistic = 674.3). These comparative data and associated 95% CIs also are

presented

in Figure 1.

Cardiovascular event-free survival according to increasing quintiles of each

individual variable and ratios of total cholesterol to HDL-C and apolipoprotein

B100

to apolipoprotein A-I appear in Figure 2. The HRs and 95% CIs for future

cardiovascular events after classifying baseline high-sensitivity CRP levels by

clinical cut points (<1, 1-3, and >3 mg/L) and baseline levels of non–HDL-C and

apolipoprotein B100 and ratios of total cholesterol to non–HDL-C and

apolipoprotein

B100 to apolipoprotein A-I by tertile, after adjustment for age (years), blood

pressure (Framingham categories), body mass index, diabetes, and current smoking

status appear in Figure 3. Similar additive effects for high-sensitivity CRP

were

observed in corresponding analyses for total cholesterol and LDL-C and the

ratios of

LDL-C to HDL-C and apolipoprotein B100 to non–HDL-C (data not shown).

We observed no evidence of effect modification for high-sensitivity CRP by age.

In

stratified analyses, the fully adjusted HR for those in the highest compared

with

the lowest quintile of high-sensitivity CRP among women younger than 55 years

was

2.9 (P = .008) while the corresponding HR for women aged 55 years or older was

2.8

(P = .002).

COMMENT

In this large, prospective cohort of initially healthy US women, we directly

compared non–HDL-C, apolipoproteins B100 and A-I, standard lipid measures, lipid

ratios, and high-sensitivity CRP as predictors of future cardiovascular events.

Overall, we observed that the magnitude of the association was greater for

apolipoprotein B100 than for either total cholesterol or LDL-C. However, we also

observed that apolipoprotein B100 was highly correlated with non–HDL-C, and that

association for non–HDL-C was effectively equal to that of apolipoprotein B100.

Moreover, the easily calculated ratio of total cholesterol to HDL-C proved to be

at

least as strongly associated with cardiovascular events as the ratio of

apolipoprotein B100 to apolipoprotein A-I. In these women, high-sensitivity CRP

also

was strongly associated with risk, but only modestly correlated with any of the

lipid parameters.

We believe these data have clinical relevance for several reasons. First, with

regard to individual lipid measures, our data are consistent with prior

prospective

cohort studies indicating that apolipoprotein B100 is a strong predictor of

risk.4-7

However, our data also indicate that apolipoprotein B100 is highly correlated

with

non–HDL-C (r = 0.87) and that the strength of association for non–HDL-C is

clinically equivalent to that of apolipoprotein B100. Thus, while differences

between apolipoprotein B100 and non–HDL-C may be of biological interest,7 our

data

do not support the use of apolipoprotein B100 in primary risk detection because

non–HDL-C can be directly calculated by subtracting HDL-C from total cholesterol

at

no incremental cost beyond usual lipid evaluation. In this regard, our data for

apolipoprotein B100 are consistent with findings from the Atherosclerosis Risk

in

Communities (ARIC) study in which apolipoprotein B100 was a univariate predictor

of

risk but did not substantively contribute to risk beyond that achievable with

standard lipid fractions.26 Consistent with both the ARIC investigation and the

Quebec Cardiovascular Study,5 we observed no substantive incremental clinical

benefit of apolipoprotein A-I evaluation over that of HDL-C.

Second, with regard to lipid ratios, our data are consistent with prior reports

that

the ratio of apolipoprotein B100 to apolipoprotein A-I is strongly associated

with

incident cardiovascular events independent of the nonlipid covariates typically

used

in global risk prediction scores.4-8 However, in a manner parallel to that

observed

for apolipoprotein B100 alone, we also observed that the strength of association

for

the ratio of apolipoprotein B100 to apolipoprotein A-I was not superior in these

data to the ratio of total cholesterol to HDL-C. Thus, on the basis of the data

in

this large prospective cohort of initially healthy women as well as other nested

case-control studies that have found the ratio of total cholesterol to HDL-C to

perform favorably,12, 27 it would not seem clinically important to replace

standard

lipid measures with more complex apolipoprotein evaluations—at least for the

purpose

of primary risk detection. On the other hand, our data and those of several

prior

studies do suggest that the use of either the ratio of total cholesterol to

HDL-C or

LDL-C to HDL-C is superior to the use of total cholesterol or LDL-C alone, and

thus

do not support the position taken by the European SCORE project, which advocates

the

use of total cholesterol in isolation.3

In the current data, the HR for those in the top vs bottom quintile of

high-sensitivity CRP was 2.98 (95% CI, 1.90-4.67), which was greater than that

of

both non–HDL-C (HR, 2.51; 95% CI, 1.69-3.72) and apolipoprotein B100 (HR, 2.50;

95%

CI, 1.68-3.72). In contrast to the strong correlations observed between lipid

measures, the correlation coefficients between high-sensitivity CRP and each

lipid

parameter were smaller and ranged from –0.33 to 0.15. These observations are

consistent with the hypothesis that both inflammation and hyperlipidemia

contribute

jointly to the atherothrombotic process. At the same time, the LR statistic in

these

data for high-sensitivity CRP was greater than that of total cholesterol and

LDL-C,

but less than that of non–HDL-C and apolipoprotein B100. This latter observation

suggests somewhat greater correlations for high-sensitivity CRP than for

standard

lipids with the nonlipid variables used in our multivariable adjustments, which

included both diabetes and obesity. These effects are not surprising because

high-sensitivity CRP levels also predict the onset of type 2 diabetes and

adipocytes

are a proinflammatory tissue.28-29

Our analysis used state-of-the art assays for all measures (including

apolipoproteins A-I and B100) and thus are unlikely to be affected by laboratory

issues that have been raised in some earlier studies of both lipid and

inflammatory

biomarkers. Furthermore, the large-scale prospective cohort approach taken

greatly

reduces the possibility of chance and bias as alternative explanations for our

findings.

However, our study does have some limitations that merit consideration. We

evaluated

plasma levels only once and thus our data may be susceptible to intra-individual

variation. Our study also evaluated middle-aged women and it is known that

adverse

effects on several blood variables can occur during and after menopause.

However,

our main findings are consistent with those from a nested case-control study

performed within the Nurses’ Health Study in which the average age of women

evaluated was older.27 Our lipid-based data are also consistent with prior

studies

conducted predominantly or exclusively among men.12, 26 Finally, we do not have

full

assessment of triglyceride levels among these women and thus cannot evaluate

whether

any of the other parameters measured might have greater or lesser value among

those

with altered triglyceride patterns.

While our analyses support the use of standard lipid measures rather than

apolipoproteins A-I and B100 in primary risk detection, these data should not be

construed to exclude a potential role for apolipoprotein B100 or the ratio of

apolipoprotein B100 to apolipoprotein A-I in monitoring patients taking statins.

In

this regard, there was virtually no use of statin therapy at the time of

enrollment

into the WHS and overall usage rates remained very low at all points of

follow-up

reflecting the low-risk nature of this cohort.19 However, in the Air Force Texas

Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a randomized trial

of

lovastatin, the levels of apolipoprotein B100 when participants were receiving

treatment and the ratio of apolipoprotein B100 to apolipoprotein A-I were better

predictors of future cardiovascular events than LDL-C.30 Levels of

apolipoproteins

B100 and A-I while participants were receiving treatment also have been found to

significantly predict recurrent cardiovascular events in several secondary

prevention studies.8, 31-32 It has been hypothesized on this basis that the

monitoring of apolipoprotein B100 could replace the current standard lipid

profile

evaluation among patients taking statins.33 With regard to high-sensitivity CRP,

recent data suggest potential utility for this inflammatory biomarker as an

adjunctive method to monitor statin efficacy not as a replacement for

LDL-C.34-36

The possible role of combined apolipoprotein and high-sensitivity CRP evaluation

to

monitor patients taking statins needs to be evaluated.

Financial Disclosures: Dr Ridker is listed as a coinventor on patents held by

the

Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers

in

cardiovascular disease. No other authors reported financial disclosures.

Al Pater, PhD; email: old542000@...

____________________________________________________

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