Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7255.199 (Published 22 July 2000) Cite this as: BMJ 2000;321:199
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EDITOR - The study of Danesh et al1 demonstrates a link between
atherosclerosis and a systemic chronic inflammatory process. The authors
conclude that the correlation of systemic inflammatory markers with future
manifestations of coronary heart disease indicates that atherosclerosis
may be a product of factors "triggering such low grade inflammation years
in advance of disease". However, cause and effect have not been
demonstrated and it is equally possible that atherosclerotic lesions are
themselves the trigger, rather than the result, of systemic inflammation.
Although manifesting in late adult life, atherosclerotic disease is
predisposed to at birth and is shown to commence in childhood and reach
marked inflammatory stages by early adulthood2. Progression, as outlined
by Ross's well-recognised model, is a result of continued damage to
endothelium overlying lesions by traditional risk factors, coupled with
intramural cytokine expression mediating further localised inflammatory
amplification3. Such inflammatory intima may be the source of those
cytokines (IL-6, TNF-alpha) known to induce systemic inflammatory change,
as discussed by Koenig in relation to the correlation of plasma levels of
these cytokines with risk of death from coronary heart disease4. This
implicates chronic low-grade systemic inflammation as a marker for
arterial lesions demonstrating an increased propensity to progress and
manifest clinically, rather than as a risk in itself for atherosclerotic
development or progression.
Faisal F Syed
4th year medical student
Laboratory Medicine Academic Group, University of Manchester, Manchester
M13 9PT
Ian SD Roberts
Consultant Pathologist
Department of Cellular Pathology, John Radcliffe Hospital, Headington,
Oxford OX3 9DU
1. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et
al. Low grade inflammation and coronary heart disease: prospective study
and updated meta-analyses. BMJ 2000;321:199-204. (22 July.)
2. Stary HC. The sequence of cell and matrix changes in
atherosclerotic lesions of coronary arteries in the first forty years of
life. Eur Heart J 1990;11 Suppl E:3-19.
3. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med
1999;340(2):115-26.
4. Koenig W. Heart disease and the inflammatory response: although
it's an integral part of the atherosclerotic process we still don't know
why. BMJ 2000;321:187-8. (22 July.)
Competing interests: No competing interests
EDITOR—We would like to compliment John Danesh and colleagues1 on the
interesting study published in BMJ regarding the role of low-grade
inflammation and coronary heart disease and add further observations. In
their study the authors suggest that some inflammatory processes are
likely to be involved in coronary heart disease. Though the mechanism
responsible for this increased risk was unclear. Taken together, these
data suggest that it may be time to add a marker of inflammation to the
list of cardiovascular risk factors commonly used to assess risk in
healthy subjects. C-reactive protein (CRP) is a good candidate because
levels are affected by little other than inflammation;2 prediction is
independent of other known cardiovascular risk factors;3 prediction
appears additive to other non-invasive measures of subclinical
atherosclerotic disease;4 and sensitive, inexpensive assays are becoming
available.
Before it can be put into general use, however, there are several
outstanding issues remaining. CRP levels predicted events in middle-aged
men, with no indication of an interaction with time to event. CRP levels
may reflect something fundamental about the patient's inflammation system:
CRP levels would identify those patients whose inflammation system
responds most actively to stimuli. These might be the patients at highest
risk for subsequent cardiovascular event or vascular death, in whom more
aggressive therapy and clinical surveillance might be appropriate.
To make some light on this issue, we investigate whether CRP levels remain
elevated at discharge and whether persistent elevation is associated with
outcome in 128 first-ever ischaemic stroke patients (53 men; mean age*SD:
73+9 years) included in a prospective hospital based stroke data bank
conducted March 1998 through December '98. We measured level of CRP within
24 hours after stroke and at hospital discharge (mean*SD 12*5 days). At
discharge, CRP was elevated (>0.5 mg/dL) in 52.3% of patients; of
these, 88.1% had elevated levels within 24 hours after stroke. Only 9.8%
of patients with discharge levels of CRP <_0.5 mg="mg" dl="dl" but="but" _50.7="_50.7" of="of" those="those" with="with" elevated="elevated" crp="crp" p.0001="p.0001" log-rank="log-rank" test="test" dead="dead" or="or" had="had" a="a" new="new" non-fatal="non-fatal" vascular="vascular" event.="event." combined="combined" end-point="end-point" occurred="occurred" in="in" _4.9="_4.9" patients="patients" lower="lower" _0.3="_0.3" _25.9="_25.9" the="the" intermediate="intermediate" tertile="tertile" _0.4-2.2="_0.4-2.2" and="and" _77.4="_77.4" upper="upper" _="_"/>2.2 mg/dL). CRP
levels >0.5 mg/dL at discharge had an adjusted odds ratio (for age,
stroke subtypes, Canadian Neurological Stroke Scale score, diabetes
mellitus, hypercholesterolaemia, fibrinogen level > 400 mg/dL, and
history of smoking, coronary heart disease, atrial fibrillation, and
arterial hypertension) for death or new non-fatal vascular event of 8.7
(95% confidence intervals 2.5 to 35.3) within one year; but of 15.8 (95%
confidence intervals 2.08 to 120.12) within 90 days, 13.1 (95% confidence
intervals 2.8 to 60.9) within 91-180 days, and of 6.39 (95% confidence
intervals 1.8 to 22.8), over 180 days.
We speculate that stroke patients in whom the inflammation system
reacts most intensely may be at greater risk for subsequent vascular
events or death. In this way a stroke may serve as a stress test of the
reactivity of the inflammation system. It would be hypothetically valuable
to have a safe way to identify whose inflammation system reacts most
actively. CRP could be a useful marker because persistent elevation of CRP
can identify a group of patients at higher risk who therefore may benefit
from more a careful clinical follow-up and appropriate antithrombotic and
possibly anti-inflammatory treatment.
Mario Di Napoli, Consultant neurologist
Francesca Papa, Consultant neurologist
Vittorio Bocola, Consultant neurologist
Department of Neurology and Neurorehabilitation,
Casa di Cura Villa Pini d'Abruzzo,
Via dei Frentani, 228,
66100 - Chieti,
Italy
Corresponding author:
Dr. MARIO DI NAPOLI, MD
E-mail: mariodinapoli@katamail.com
References
1. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al.
Low grade inflammation and coronary herath disease: prospective study and
updated meta-analyses. BMJ 2000; 321: 199-204.
2. Pepys M. C-reactive protein fifty years on. Lancet 1981; i: 653-
656.
3. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the
predictive value of total and HDL cholesterol in determining risk of first
myocardial infarction. Circulation 1998; 97: 2007-2011.
4. Tracy R, Lemaitre R, Psaty B, Ives D, Evans R, Cushman M, et al.
Relationship of C-reactive protein to risk of cardiovascular disease in
the elderly: results from the Cardiovascular Health Study and the Rural
Health Promotion Project. Arterioscler Thromb Vasc Biol 1997; 17: 1121-
1127.
Competing interests: No competing interests
All three studies published on coronary heart disease use death certification as a certain outcome.
The use of the words "myocardial infarction" on a death certificate means that the patient has collapsed, that there are no suspicious circumstances and that coronary artery occlusion is an unarguable conclusion for the purposes of that exercise. To use that sworn statement as evidence of the presence of coronary artery disease is another matter.
Unless all the deaths were followed by a postmortem ( unlikely) then death certification is a totally unreliable measure on which to base these conclusions
Competing interests: No competing interests
Association of Chlamydia pneumoniae IgG titres and cardiovascular diseases.
Dear Sir - One of the underlying pathologies of cardiovascular
diseases is atherosclerosis, a process continuing from days to decades
encompassing at least three different phases: initiation, progression, and
complications. A different set of risk factors is associated with each
phase. The interest in infections as risk factor has been revived in the
past decade by many reports. A recent issue of the BMJ devotes several
papers on this topic (1). Experience with Chlamydia pneumoniae research is
limited and diagnostics are not standardised. Therefore, study reports
should be communicated carefully.
Although the microimmunofluorescence antibody test is considered the gold
standard, specialised research laboratories have 54%-92% agreement in
results of single specimens (2). Thus, each laboratory will measure a
different subset of genus- and species-specific antibodies. Each test will
not be equally well suited for diagnosing both acute and chronic
infections. Previously, we have shown that a suitable test for chronic
infections should include antibodies to the chlamydial LPS (3). Most
laboratories, however, attempt to exclude these antibodies to improve
specificity for C pneumoniae (4). The test used (1 a, b, c) has not been
validated as a marker for chronic infections. Technically, it is possible
that the reactivity of the chlamydial LPS is reduced by the use of normal
goat serum and bovine g-globulin.
An epidemic of C pneumoniae lasts for 2-3 years with endemic periods of 5-
7 years. An ongoing epidemic might have a great impact on the outcome of a
case-control study since controls will have high antibody levels as well.
The time interval between the serum specimen and the event might influence
the strength of the association, since prospective studies tend to show
less strong associations than cross-sectional studies. Prospective studies
might underestimate the association since the effect of acute C pneumoniae
(re)infections on complications is not included. Also, a persistent high
level of antibodies might be more predictive than a single point
measurement. Adjustment for "known" risk factors is a controversial issue,
especially since the pathogenesis is still not clear and the studied risk
factors could be (an intermediate) involved in the disease mechanism (1 d,
5). For example, smoking cigarettes increases the incidence of respiratory
tract infections, including C pneumoniae, thus contributing to
atherogenesis. To be comprehensive, analyses should be reported with and
without adjustment for carefully described potential confounders.
In conclusion, the studies reported do not reliably exclude the existence
of any association between C pneumoniae and cardiovascular diseases.
Specific characteristics of C pneumoniae diagnostics and of the
epidemiology of acute and chronic infections should be included in the
analyses.
J.M. Ossewaarde
Research Laboratory for Infectious Diseases,
National Institute for Public Health and the Environment,
PO Box 1,
3720 BA Bilthoven,
The Netherlands
D.G.M. Bloemenkamp
Y. van der Graaf
Julius Center for Patient Oriented Research
University Medical Center Utrecht
PO Box 85500
3508 GA Utrecht
The Netherlands
References
1a Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P,
Gallimore JR, Pepys MB. Low grade inflammation and coronary heart disease:
prospective study and updated meta-analyses. BMJ 2000;321:199-204.
b Wald NJ, Law MR, Morris JK, Zhou X, Wong Y, Ward ME. Chlamydia
pneumoniae infection and mortality from ischaemic heart disease: large
prospective study. BMJ 2000;321:204-7.
c Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Wong
Yk, Bernardes-Silva M, Ward M. Chlamydia pneumoniae IgG titres and
coronary heart disease: prospective study and meta-analysis. BMJ
2000;321:208-13.
d West R. Commentary: Adjustment for potential confounders may have
been taken too far. BMJ 2000;321:213.
2 Peeling RW, Wang SP, Grayston JT, Blasi F, Boman J, Clad A,
Freidank H, Gaydos CA, Gnarpe J, Hagiwara T, Jones RB, Orfila J, Persson
K, Puolakkainen M, Saikku P, Schachter J. Chlamydia pneumoniae serology:
interlaboratory variation in microimmunofluorescence assay results. J
Infect Dis 2000;181 Suppl 3:S426-9.
3 Ossewaarde JM, Feskens EJ, De Vries A, Vallinga CE, Kromhout D.
Chlamydia pneumoniae is a risk factor for coronary heart disease in
symptom-free elderly men, but Helicobacter pylori and cytomegalovirus are
not. Epidemiol Infect 1998;120:93-9.
4 Ossewaarde JM, Manten JW, Hooft HJ, Hekker AC. An enzyme
immunoassay to detect specific antibodies to protein and
lipopolysaccharide antigens of Chlamydia trachomatis. J Immunol Methods
1989;123:293-8.
5 Day NE, Byar DP, Green SB. Overadjustment in case-control studies.
Am J Epidemiol 1980;112:696-706.
Competing interests: No competing interests