LE Magazine December 2002
C-reactive protein
Lack of association between
cholesterol and coronary heart disease mortality and morbidity
and all-cause mortality in persons older than 70 years.
OBJECTIVES: To determine whether elevated serum cholesterol
level is associated with all-cause mortality, mortality from
coronary heart disease, or hospitalization for acute
myocardial infarction and unstable angina in persons older
than 70 years. Also, to evaluate the association between low
levels of high-density lipoprotein cholesterol (HDL-C) and
elevated ratio of serum cholesterol to HDL-C with these
outcomes. DESIGN: Prospective, community-based cohort study
with yearly interviews. PARTICIPANTS--A total of 997 subjects
who were interviewed in 1988 as part of the New Haven, Conn.
cohort of the Established Population for the Epidemiologic
Study of the Elderly (EPESE) and consented to have blood
drawn. MAIN OUTCOME MEASURES: The risk factor-adjusted odds
ratios of the four-year incidence of all-cause mortality,
mortality from coronary heart disease, and hospitalization for
myocardial infarction or unstable angina were calculated for
the following: subjects with total serum cholesterol levels
greater than or equal to 6.20 mmol/L (> or = 240 mg/dL)
compared with subjects with cholesterol levels less than 5.20
mmol/L (< 200 mg/dL); subjects in the lowest tertile of
HDL-C level compared with those in the highest tertile; and
subjects in the highest tertile of the ratio of total serum
cholesterol to HDL-C level compared with those in the lowest
tertile. RESULTS: Elevated total serum cholesterol level, low
HDL-C, and high total serum cholesterol to HDL-C ratio were
not associated with a significantly higher rate of all-cause
mortality, coronary heart disease mortality or hospitalization
for myocardial infarction or unstable angina after adjustment
for cardiovascular risk factors. The risk factor-adjusted odds
ratio for all-cause mortality was 0.99 (95% confidence
interval [CI], 0.56 to 2.69) for the group who had cholesterol
levels greater than or equal to 6.20 mmol/L (> or = 240
mg/dL) compared with the group that had levels less than 5.20
mmol/L (< 200 mg/dL); 1.00 (95% CI, 0.59 to 1.70) for the
group in the lowest tertile of HDL-C compared with those in
the highest tertile; and 1.03 (95% CK, 0.62 to 1.71) for
subjects in the highest tertile of the ratio of total serum
cholesterol to HDL-C compared with those in the lowest
tertile. CONCLUSIONS: Our findings do not support the
hypothesis that hypercholesterolemia or low HDL-C are
important risk factors for all-cause mortality, coronary heart
disease mortality or hospitalization for myocardial infarction
or unstable angina in this cohort of persons older than 70
years.
JAMA 1994 Nov 2;272(17):1335-40
Report of the conference on low blood
cholesterol: mortality associations.
BACKGROUND: A National Heart, Lung and Blood Institute
(NHLBI) Conference was held October 9-10, 1990, to review and
discuss existing data on U-shaped relations found between
mortality rates and blood total cholesterol levels (TC) in
some but not other studies. Presentations were given from 19
cohort studies from the United States, Europe, Israel and
Japan. A representative of each study presented its findings
and also submitted tables of proportional hazards regression
coefficients for entry TC levels in regard to death, and these
were incorporated into a formal statistical overview adjusted
for age, diastolic blood pressure, cigarette smoking, body
mass index and alcohol intake, as available. METHODS AND
RESULTS: The U-shape for total mortality in men and the flat
relation in women resulted largely from a positive relation of
TC with coronary heart disease death and an inverse relation
with deaths caused by some cancers (e.g., lung but not colon),
respiratory disease, digestive disease, trauma and residual
deaths. Risk for combined noncardiovascular, noncancer causes
of death decreased steadily across the range of TC. The
conference considered possible explanations for the
statistical associations found between low TC levels or active
TC lowering and certain causes of death. One is that TC is
lowered by some disease conditions themselves, such as wasting
in chronic pulmonary disease or reduced production and
secretion of cholesterol-bearing lipoproteins with liver
disease. In this sort of situation, the TC:mortality
association found in observational studies may be due to
preexisting disease. This was addressed by excluding early
deaths from the analysis, which did not change the results.
The conference considered as well the biological function of
cholesterol, which, if seriously deranged, might
hypothetically cause a wide variety of diseases and
dysfunction. The conference also considered the biological
functions that might provide plausible mechanisms for the
associations found. CONCLUSIONS: Definitive interpretation of
the associations observed was not possible, although most
participants considered it likely that many of the statistical
associations of low or lowered TC level are explainable by
confounding in one form or another. The conference focused on
the apparent existence and nature of these associations and on
the need to understand their source rather than on any
pertinence of the findings for public health policy. Further
research is recommended to explain the observed associations
of low TC levels (and TC lowering) with certain
noncardiovascular diseases. This includes studies of the time
course of TC change in disease, the relation of TC to
morbidity, further studies of possible epidemiological
confounding, monitoring of population trends in TC and
mortality, further studies of the relations in women, auditing
of noncardiovascular events in trials, studies of cell
membrane, genetic and molecular links to cholesterol
metabolism, TC level and disease, studies of disease
manifestations in specific lipid disorders, and further study
of the proposed causal mechanisms linking low TC and
hemorrhagic stroke.
Circulation 1992
Sep;86(3):1046-60
Inflammatory markers and coronary
heart disease.
PURPOSE OF REVIEW: Despite changes in lifestyle and the use
of effective pharmacologic interventions to lower cholesterol
levels, coronary heart disease remains the major cause of
morbidity and mortality in the developed world. Cholesterol
screening fails to identify almost 50% of those individuals
who will present with acute coronary syndromes. Recent
evidence from laboratory and prospective clinical studies
demonstrates that atherosclerosis is not simply a disease of
lipid deposition, but rather is an inflammatory process with
highly specific cellular and molecular responses. The clinical
utility of inflammatory markers has been examined in a variety
of atherothrombotic diseases. Because C-reactive protein is
highly stable in stored frozen samples, and automated and
robust analytical systems for its measurement are available,
it has become the most widely examined inflammatory marker.
RECENT FINDINGS: C-reactive protein has consistently been
shown to be a useful prognostic indicator in acute coronary
syndromes and is a strong predictor of future coronary events
in apparently healthy individuals. In addition, C-reactive
protein can identify individuals with normal lipid levels who
are at increased risk for future coronary events. Because
drugs such as aspirin and statins reduce inflammatory risk,
C-reactive protein has the potential to guide the use of these
therapies in high-risk individuals for primary prevention.
SUMMARY: C-reactive protein may have a role in global risk
assessment for primary prevention and in targeting those
patients who will benefit from anti-inflammatory therapies. In
addition, it may also be a good prognostic indicator in
patients with acute coronary syndromes.
Curr Opin Lipidol 2002
Aug;13(4):383-9
Prospective study of C-reactive
protein, homocysteine and plasma lipid levels as predictors of
sudden cardiac death.
BACKGROUND: Sudden cardiac death (SCD) is an important
cause of mortality even among apparently healthy populations.
However, our ability to identify those at risk for SCD in the
general population is poor, and more specific markers are
needed. METHODS AND RESULTS: To compare and contrast the
relative importance of C-reactive protein (CRP), homocysteine
and lipids as long-term predictors of SCD, we performed a
prospective, nested, case-control analysis involving 97 cases
of SCD among apparently healthy men enrolled in the
Physician’s Health Study. Of these plasma markers
measured, only baseline CRP levels were significantly
associated with the risk of SCD over the ensuing 17 years of
follow-up (P for trend=0.001). The increase in risk associated
with CRP levels was primarily seen among men in the highest
quartile, who were at a 2.78-fold increased risk of SCD (95%
CI 1.35 to 5.72) compared with men in the lowest quartile.
These results were not significantly altered in analyses that
(in addition to the matching variables of age and smoking
status) controlled for lipid parameters, homocysteine, and
multiple cardiac risk factors (relative risk for highest
versus lowest quartile 2.65, 95% CI 0.79 to 8.83; P for
trend=0.03). In contrast to the positive relationship observed
for CRP, neither homocysteine nor lipid levels were
significantly associated with risk of SCD. CONCLUSIONS: These
prospective data suggest that CRP levels may be useful in
identifying apparently healthy men who are at an increased
long-term risk of SCD.
Circulation 2002 Jun
4;105(22):2595-9
C-reactive protein, statins and the
primary prevention of atherosclerotic cardiovascular
disease.
Emerging data implicate inflammation as integral to
atherosclerosis and its complications. From a clinical
perspective, the inflammatory biomarker C-reactive protein has
demonstrated consistent predictive value in the detection of
individuals at high risk for cardiovascular disease. Therapy
with 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statins) reduces C-reactive protein as well as
low-density lipoprotein cholesterol, thus providing a
potential additional mechanism for the reduction in
cardiovascular events associated with the use of these agents.
Evidence from the Air Force/Texas Coronary Atherosclerosis
Prevention Study suggests that statin therapy may be effective
in reducing incident coronary events among those with elevated
levels of C-reactive protein but normal levels of low-density
lipoprotein cholesterol. These data, along with accumulating
laboratory data, support a potential anti-inflammatory benefit
of statins. Large-scale, randomized trials in the primary
prevention of acute coronary events among individuals without
overt hyperlipidemia but with evidence of elevated C-reactive
protein are now needed to directly test this hypothesis.
Prev Cardiol 2002
Winter;5(1):42-6
Inflammatory mechanisms in
atherosclerosis: from laboratory evidence to clinical
application.
From the initial stages of leukocyte recruitment to
diseased endothelium, to eventual rupture of unstable
atheromatous plaque, pro-inflammatory mechanisms mediate key
steps in atherogenesis and its complications. Lipid lowering,
both with diet and statin therapy, has been shown to have
favorable effects on inflammatory processes in atheromatous
plaque. Several plasma markers of inflammation have been found
to predict future cardiovascular risk, both among patients
with acute coronary syndromes and myocardial infarction, and
among healthy men and women. C-reactive protein (CRP), a
pattern recognition molecule linked to the innate immune
system, is a sensitive marker of low-grade vascular
inflammation, which may also have direct pro-inflammatory
actions. Recent studies have shown that statin therapy may
lower CRP levels independent of lipid-lowering effects. Statin
therapy may also be highly effective for the prevention of
cardiovascular events among individuals with elevated CRP
levels. The role of statin therapy for plaque stabilization in
acute coronary syndromes, and for prevention of future plaque
rupture among healthy individuals with evidence of vascular
inflammation, is an area of active research.
Ital Heart J 2001
Nov;2(11):796-800
Inflammatory biomarkers, hormone
replacement therapy and incident coronary heart disease:
prospective analysis from the Women’s Health Initiative
observational study.
CONTEXT: Postmenopausal hormone replacement therapy (HRT)
has been shown to elevate C-reactive protein (CRP) levels.
Several inflammatory biomarkers, including CRP, are associated
with increased cardiovascular risk. However, whether the
effect of HRT on CRP represents a clinical hazard is unknown.
OBJECTIVES: To assess the association between baseline levels
of CRP and interleukin 6 (IL-6) and incident coronary heart
disease (CHD) and to examine the relationship between baseline
use of HRT, CRP, and IL-6 levels as they relate to subsequent
vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Prospective,
nested case-control study of postmenopausal women, forming
part of the Women’s Health Initiative, a large,
nationwide, observational study. Among 75,343 women with no
history of cardiovascular disease or cancer, 304 women who
developed incident CHD were defined as cases and matched by
age, smoking status, ethnicity, and follow-up time with 304
study participants who remained event free during a median
observation period of 2.9 years. MAIN OUTCOME MEASURE:
Incidence of first myocardial infarction or death from CHD.
RESULTS: Median baseline levels of CRP (0.33 vs 0.25 mg/dL;
interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001)
and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15;
P<.001) were significantly higher among cases compared with
controls. In matched analyses, the odds ratio (OR) for
incident CHD in the highest vs lowest quartile was 2.3 for CRP
(95% confidence interval [CI], 1.4-3.7; P for trend =.002) and
3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After
additional adjustment for lipid and nonlipid risk factors,
both inflammatory markers were significantly associated with a
two-fold increase in odds for CHD events. As anticipated,
current use of HRT was associated with significantly elevated
median CRP levels. However, there was no association between
HRT and IL-6. In analyses comparing individuals with
comparable baseline levels of either CRP or IL-6, those taking
or not taking HRT had similar CHD ORs. In analyses stratified
by HRT, we observed a positively graded relationship between
plasma CRP levels and the OR for CHD among both users and
nonusers of HRT across the full spectrum of baseline CRP.
CONCLUSIONS: These prospective findings indicate that CRP and
IL-6 independently predict vascular events among apparently
healthy postmenopausal women and that HRT increases CRP.
However, use or nonuse of HRT had less importance as a
predictor of cardiovascular risk than did baseline levels of
either CRP or IL-6.
JAMA 2002 Aug 28;288(8):980-7
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