Michael A. Mendall

C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study.

Abstract Objective: To test the hypothesis that minor chronic insults such as smoking, chronic bronchitis, and two persistent bacterial infections may be associated with increases in C reactive protein concentration within the normal range and that variations in the C reactive protein concentration in turn may be associated with levels of cardiovascular risk factors and chronic coronary heart disease. Design: Population based cross sectional study. Setting: General practices in Merton, Sutton, and Wandsworth. Subjects: A random sample of 388 men aged 50-69 years from general practice registers. 612 men were invited to attend and 413 attended, of whom 25 non-white men were excluded. The first 303 of the remaining 388 men had full risk factor profiles determined. Interventions: Measurements of serum C reactive protein concentrations by in house enzyme linked immunosorbent assay (ELISA); other determinations by standard methods. Coronary heart disease was sought by the Rose angina questionnaire and Minnesota coded electrocardiograms. Main outcome measures: Serum C reactive protein concentrations, cardiovascular risk factor levels, and the presence of coronary heart disease. Results: Increasing age, smoking, symptoms of chronic bronchitis, Helicobacter pylori and Chlamydia pneumoniae infections, and body mass index were all associated with raised concentrations of C reactive protein. C Reactive protein concentration was associated with raised serum fibrinogen, sialic acid, total cholesterol, triglyceride, glucose, and apolipoprotein B values. C Reactive protein concentration was negatively associated with high density lipoprotein cholesterol concentration. There was a weaker positive relation with low density lipoprotein cholesterol concentration and no relation with apolipoprotein A I value. C Reactive protein concentration was also strongly associated with coronary heart disease. Conclusion: The bodys response to inflammation may play an important part in influencing the progression of atherosclerosis. The association of C reactive protein concentration with coronary heart disease needs testing in prospective studies. Key messages Factors that determine levels of inflammatory mediators in the normal general population have not been explored, nor has their relation to cardio- vascular risk factors Among 50-69 year old men many environmental and lifestyle risk factors for cardiovascular disease are associated with raised serum concentrations of C reactive protein Circulating concentrations of lipids, glucose, and clotting factors are also associated with serum C reactive protein concentrations The bodys response to inflammation may influence the development of atherosclerosis

Elevated Chlamydia pneumoniae Antibodies, Cardiovascular Events, and Azithromycin in Male Survivors of Myocardial Infarction

Background The clinical significance of the association between elevated anti– Chlamydia pneumoniae (Cp) antibody titres and coronary heart disease (CHD) is unclear. We explored the relationship between antibodies against Cp and future cardiovascular events in male survivors of myocardial infarction (MI). The effect of azithromycin antibiotic therapy was assessed in a subgroup of post-MI patients. Methods and Results We screened 220 consecutive male survivors of MI for anti-Cp antibodies. Of these, 213 patients were stratified into three groups: group Cp-ve (n=59), no detectable Cp antibodies; group Cp-I (n=74), intermediate titres of 1/8 to 1/32 dilution; and group Cp+ve (n=80), seropositive at ≥1/64 dilution. Patients with persisting seropositivity of ≥1/64 were randomized to either oral azithromycin (Cp+ve-A, 500 mg/d for 3 days [n=28] or 500 mg/d for 6 days [n=12]) or placebo (Cp+ve-P, n=20). Cp+ve-NR (n=20) represented patients not recruited into the antibiotic trial. The incidence of adverse cardiovascular events (over a mean follow-up period of 18±4 months) was recorded and shown to increase with increasing anti-Cp titre: Cp-ve, n=4 (7%); Cp-I, n=11 (15%); Cp+ve-NR, n=6 (30%); and Cp+ve-P, n=5 (25%). Cp+ve-NR and Cp+ve-P groups had a fourfold-increased risk for adverse cardiovascular events compared with the Cp-ve group (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2 to 15.5; P =.03). In contrast, the OR for cardiovascular events in patients receiving azithromycin (Cp+ve-A, single or double course) was the same as in the Cp-ve group (OR, 0.9; 95% CI, 0.2 to 4.6, P =NS). Patients receiving azithromycin were more likely to experience a decrease in IgG anti-Cp titres than were those in the placebo group ( P =.02). Conclusions An increased anti-Cp antibody titre may be a predictor for further adverse cardiovascular events in post-MI patients. Taking a short course of azithromycin may lower this risk, possibly by acting against Cp.

Relation of Helicobacter pylori infection and coronary heart disease.

BACKGROUND--There is evidence suggesting that early life experience may influence adult risk of coronary heart disease (CHD). Chronic bacterial infections have been associated with CHD. OBJECTIVE--To determine whether Helicobacter pylori, a childhood acquired chronic bacterial infection, is associated with an increased risk of coronary heart disease in later life. DESIGN--Case-control study controlling for potential confounding variables with an opportunistically recruited control group. SUBJECTS--111 consecutive cases with documented CHD were recruited from a cardiology clinic and 74 controls from a general practice health screening clinic. All were white men aged 45-65. METHODS--Serum was analysed for the presence of H pylori specific IgG antibodies by ELISA (98% sensitive and 94% specific for the presence of infection). RESULTS--59% of the cases and 39% of the controls were seropositive for H pylori (odds ratio 2.28, chi 2 7.35, p = 0.007). After adjustment by multiple logistic regression for age, cardiovascular risk factors, and current social class, the effect of H pylori was little altered (odds ratio 2.15, p = 0.03). Further adjustment for various features of the childhood environment known to be risk factors for H pylori infection only slightly weakened the association (odds ratio 1.9). H pylori seropositivity was not related to the level of risk factors in the control population. CONCLUSION--In this pilot study the association of adult coronary heart disease with H pylori seropositivity suggests that the early childhood environment may be important in determining the risk of CHD in adult life. The association needs confirmation in other better designed studies. If H pylori itself is responsible for the association, then this is of great potential importance as the infection is treatable.

Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors.

Abstract Objective: To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Objective:To investigate the relation between seropositivity to chronic infections with Helicobacter pylori and Chlamydia pneumoniae and both coronary heart disease and cardiovascular risk factors. Setting: General practices in Merton, Sutton, and Wandsworth, south London. Subjects: 388 white south London men aged 50-69. Main outcome measures: Evidence of coronary risk factors and infection with H pylori or C pneumoniae. Results: 47 men (12.1%) had electrocardiographic evidence of ischaemia or infarction. 36 (76.6%) and 18 (38.3%) were seropositive for H pylori and C pneumoniae, respectively, compared with 155 (45.5%) and 62 (18.2%) men with normal electrocardiograms. Odds ratios for abnormal electrocardiograms were 3.82 (95% confidence interval 1.60 to 9.10) and 3.06 (12.33 to 7.01) in men seropositive for H pylori and C pneumoniae, respectively, after adjustment for a range of socioeconomic indicators and risk factors for coronary heart disease. Cardiovascular risk factors that were independently associated with seropositivity to H pylori included fibrinogen concentration and total leucocyte count. Seropositivity to C pneumoniae was independently associated with raised fibrinogen and malondialdehyde concentrations. Conclusions: Both H pylori and C pneumoniae infections are associated with coronary heart disease. These relations are not explained by a wide range of confounding factors. Possible mechanisms include an increase in risk factor levels due to a low grade chronic inflammatory response.

Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease.

OBJECTIVE: To determine whether serum concentrations of the cytokines tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which regulate C reactive protein, are associated with cardiovascular risk factors and prevalent coronary heart disease. DESIGN: A population based cross sectional study. SUBJECTS AND METHODS: 198 men aged 50 to 69 years were part of a random population sample drawn from south London. Serum cytokine and C reactive protein concentrations were determined by enzyme linked immunosorbent assay. The presence of coronary heart disease was determined by Rose angina questionnaire and Minnesota coded electrocardiogram. RESULTS: Serum TNF alpha concentrations were positively related to body mass index and Helicobacter pylori infection, but inversely related to alcohol consumption. IL-6 concentrations were positively associated with smoking, symptoms of chronic bronchitis, age, and father having a manual occupation. TNF alpha was associated with increased IL-6 and triglycerides, and reduced high density lipoprotein cholesterol. IL-6 was associated with raised fibrinogen, sialic acid, and triglycerides. ECG abnormalities were independently associated with increases in IL-6 and TNF alpha, each by approximately 50% (P < 0.05 for TNF alpha, P < 0.1 for IL-6). The corresponding increases in men with an abnormal ECG or symptomatic coronary heart disease were 28% for TNF alpha and 36% for IL-6 (P = 0.14 for TNF alpha and P < 0.05 for IL-6). CONCLUSIONS: This study confirms that many of the phenomena with which C reactive protein is associated, are also associated with serum levels of cytokine, which may be the mechanism.

Helicobacter pylori infection in childhood: risk factors and effect on growth

Abstract Objective: To investigate the current prevalence of Helicobacter pylori infection in childhood, the risk factors for infection, and the effect of infection on growth in preadolescent schoolchildren. Design: Population based sample of 7 year old schoolchildren followed up at age 11; data on risk20factors for infection collected at age 7; presence of infection at age 11 determined by measurement of salivary IgG against H pylori by a newly developed enzyme linked immunosorbent assay (ELISA). Height was measured at 7 and 11 years of age. Subjects: 554 schoolchildren from Edinburgh. Results: 62 (11%) children had H pylori infection.20Independent risk factors for infection were single parent families (adjusted odds ratio=2.5; 95% confidence interval 1.1 to 5.7), the 10% most crowded homes (3.1; 1.3 to 7.2), and schools serving predominantly rented housing estates (2.5; 1.0 to 6.5). School catchment area was more important than parental social class or housing tenure. Growth in height between 7 and 11 was diminished in infected children by a mean of 1.1 cm (0.3 to 2.0 cm) over four years. This growth reduction was largely confined to girls (1.6 cm over four years), among whom it correlated with salivary IgG (P=0.015). Conclusion: Data from salivary assay to investigate the epidemiology of H pylori suggest that factors relating to the type of community in which the child lives may now be as important for acquisition of this infection as features of the family home. The greater reduction of growth among infected girls raises the possibility that H pylori infection may delay or diminish the pubertal growth spurt.

Chlamydia pneumoniae: Risk factors for seropositivity and association with coronary heart disease

BACKGROUND Two studies have suggested that seropositivity for Chlamydia pneumoniae (C. pneumoniae) is a risk factor for coronary heart disease (CHD) but the association remains tenuous. Further data is required in other populations to consolidate this observation. AIMS Initially to determine descriptive risk factors for C. pneumoniae seropositivity in a general population sample and subsequently to examine the relation of seropositivity for this organism to CHD for the first time in a British population. SETTING A single general practice health screening clinic and a cardiology clinic involving patients predominantly residing in south London and Surrey. SUBJECTS 210 consecutive caucasian men (62%) and women (38%) aged 18-79 including 67 men aged 45-65. This latter group acting as controls were then also compared with 103 consecutive males aged 45-65 with angiographically confirmed coronary heart disease. METHODS A questionnaire was administered by a research nurse and serum was analysed for IgG and IgA against C. pneumoniae and other Chlamydiae by a microimmunofluorescence test. Serum was said to be low positive at a specific IgG antibody titre of 16-32, and high positive if 64 or greater. RESULTS Amongst the general practice health screening clinic population 14 subjects (7%) were excluded due to possible cross-reactivity with other Chlamydia species (predominantly C. trachomatis). Of the remaining 196 subjects, 13 (6%) had high positive C. pneumoniae IgG titres, 68 (35%) had low titres and 125 had no detectable antibody. After adjustment for sex, age, smoking history, social class and family size only one risk factor for high positive titres in this group was identified, which was the number of children currently living in the home (OR 2.29 (1.09-4.80), P = 0.03). No factors were significantly related to low titres. 22/100 (22%) cases with coronary heart disease and 3/64 (4.7%) of controls had high positive IgG titres for C. pneumoniae. Similarly 21% of cases and 9.4% of controls had positive C. pneumoniae specific IgA serology. 45% of cases and 44% of controls had low C. pneumoniae IgG titres. The association of CHD with a C. pneumoniae IgG titre of 64 or above was independent of all risk factors (OR 7.4 (1.7-33.1), P < 0.01). CONCLUSION Serological evidence of C. pneumoniae infection is common amongst healthy British subjects. Smoking and social class are not important confounding variables in this study. Reinfection from contact with infected children in the home may be important in inducing higher titres in some subjects. These higher titres are more prevalent in subjects with coronary heart disease in the U.K. as reported in Finland and the U.S.A., and provide further evidence that C. pneumoniae may be important in the pathogenesis of this condition in these populations.

Bowel Inflammation as Measured by Fecal Calprotectin: A Link between Lifestyle Factors and Colorectal Cancer Risk

The mechanisms by which the lifestyle risk factors obesity, physical inactivity, and low fiber intake predispose to colorectal cancer (CRC) are unclear. Chronic bowel inflammation predisposes to malignancy in cases of inflammatory bowel disease. Many lifestyle risk factors for CRC are associated with evidence of systemic inflammation as indicated by circulating levels of C-reactive protein (CRP), but it is unknown how this relates to inflammation at tissue level. Little is known about the degree of bowel inflammation in general population and the factors that affect it. Therefore, we aimed to assess the relation of levels of bowel inflammation in the general population and lifestyle risk factors for CRC, and to additionally assess whether these associations, if present, were attenuated by controlling for evidence of systemic inflammation. Average CRC risk subjects (320) of either sex aged 50–70 were recruited in South London. A stool sample was provided for calprotectin measurement (a marker of bowel inflammation), serum for CRP, and a detailed dietary and lifestyle questionnaire completed. There was a significant positive relationship between fecal calprotectin and increasing age (P = 0.002), obesity (P = 0.04), physical inactivity (P = 0.01), and an inverse relationship with fiber intake (P = 0.02) and vegetable consumption (P = 0.04). The relationship with obesity was attenuated by controlling for serum CRP. Fecal calprotectin levels are associated with lifestyle risk factors for colorectal cancer. Low-level asymptomatic bowel inflammation may be the link between lifestyle and the pathogenesis of CRC, and circulating proinflammatory cytokines may be part of the mechanism for this link.

Prospective screening of dyspeptic patients by Helicobacter pylori serology.

Helicobacter pylori infection is associated with 95% of duodenal ulcers and more than 80% of gastric ulcers. Several reports have indicated that screening for H pylori may avoid subsequent endoscopic examination. We screened 183 dyspeptic patients, aged under 45, by taking a history of sinister symptoms and regular use of non-steroidal anti-inflammatory drugs (NSAIDs), together with serological testing for H pylori. Endoscopy was performed on 113 patients, of whom 90 (49%) were seropositive, 14 (8%) had sinister symptoms, and 9 (5%) had used NSAIDs regularly. In 34 (19%) patients we detected peptic ulceration. The remaining 70 (38%) patients who were H pylori seronegative, had no sinister symptoms, and had not taken NSAIDs (screen-negative), did not undergo endoscopy but were returned to their primary care physician for treatment of symptoms. At subsequent reassessment (of the non-endoscoped group), symptom severity (p = 0.002), interference with life events (p = 0.01), and medication (p = 0.0002) were all significantly lower in the 6 months after screening than in the 6 month period before screening. Only three screen-negative patients were re-referred after screening but their endoscopic findings were normal. Thus, 67 (36%) endoscopies were avoided. When the non-endoscoped screen-negative patients were compared with a cohort of endoscoped screen-negative patients, the groups did not differ in terms of symptom severity (odds ratio 1.12, 95% CI 0.53-2.35, p = 0.77) or interference with life events (0.82, 0.38-1.76, p-0.61). However, medication use was significantly less (0.37, 0.17-0.80, p = 0.01) in those who did not have an endoscopy. Our study indicates that colonisation screening based on H pylori serology, a history of sinister symptoms, or a history of NSAID use was worthwhile in dyspeptic patients. We avoided 37% of endoscopies and reduced drug usage without disadvantaging those not endoscoped.

Antibiotic use, childhood affluence and irritable bowel syndrome (IBS).

Background Antibiotics cause well defined short-lived disturbances in bowel habit There is evidence to suggest that antibiotics may play a role in the pathogenesis of IBS. Atopy has been associated with small household size in childhood and could also play a role in IBS. We conducted a survey examining the relation of drug use and other epidemiological correlates of IBS. Setting General practice health screening clinic. Subjects and methods 421 subjects (46% male, mean age 47 years (range 18–80 years) attending a general practice health screening clinic were interviewed by a research nurse and completed a previously validated questionnaire. Symptoms of IBS were said to be present if abdominal pain with 2 or more Manning criteria symptoms occurred more than once per month over the previous 6 months. Results 48 subjects had symptoms of IBS. The following were strongly related to its presence: antibiotic use [adjusted OR 3.70 (1.80–7.60)], female sex and childhood living density <1 person per room [OR 3.47 (1.57–7.64)], manual fathers occupation [OR 0.35 (0.16–0.76)]. The use of NSAIDS, H2 antagonists or other types of medication was not greater in this group. Conclusion Antibiotic use is associated with IBS. The association with antibiotic use requires testing in prospective studies. Privileged childhood living conditions were also an important risk factor which is consistent with an allergic aetiology for IBS.