Juan-Carlos Kaski

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.

Effect of Treatment for Chlamydia pneumoniae and Helicobacter pylori on Markers of Inflammation and Cardiac Events in Patients With Acute Coronary Syndromes

Background—Infection with Helicobacter pylori and Chlamydia pneumoniae is associated with coronary heart disease. We conducted an intervention study using antibiotics against these bacteria in patients with acute coronary syndromes to determine whether antibiotics reduce inflammatory markers and adverse cardiac events. Methods and Results—Patients (n=325) admitted with acute myocardial infarction or unstable angina (acute coronary syndromes) were randomized to receive a 1-week course of 1 of 3 treatment regimens: (1) placebo; (2) amoxicillin (500 mg twice daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily); or (3) azithromycin (500 mg once daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily). Serum fibrinogen, white cell count, and high-sensitivity C-reactive protein were measured at study entry and at 1, 3, and 12 months during follow-up. Cardiac death and readmission with acute coronary syndrome were considered clinical end points. Patients were followed for 1 year. C-reactive protein levels were reduced (P =0.03) in unstable angina patients receiving amoxicillin, and fibrinogen was reduced in both patient groups receiving antibiotics (P =0.06). There were 17 cardiac deaths and 71 readmissions with acute coronary syndrome. No difference in frequency or timing of end points was observed between the 2 antibiotic groups. At 12 weeks, there was a 36% reduction in all end points in patients receiving antibiotics compared with placebo (P =0.02). This reduction persisted during the 1-year follow-up. Neither C pneumoniae nor H pylori antibody status was significantly related to response to treatment. Conclusions—Antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes, but the effect was independent of H pylori or C pneumoniae seropositivity.

Chest pain and normal coronary arteriograms: role of “microvascular spasm”

Although patients with typical chest pain, ischaemic electrocardiographic (ECG) changes on exercise stress testing, and normal coronary arteriograms are commonly diagnosed as having “cardiac syndrome X” there is no consensus on the definition and pathogenesis of this disorder. Indeed, the issue is confused because some patients seem to have myocardial ischaemia and others do not. Moreover, not all patients have abnormal coronary microvascular responses to vasoactive stimuli. Such controversial findings have hampered attempts to identify a single, homogeneous pathophysiological mechanism. If any consensus has been reached after decades of research, it is that syndrome X is heterogeneous and may encompass diverse pathogenetic entities. The syndrome has been attributed to oesophageal abnormalities, increased pain perception, left-ventricular hypertrophy, systemic hypertension, oestrogen deficiency, and endothelial dysfunction. In this issue of The Lancet Masahiro Mohri and colleagues describe what seems to be yet another subset of patients with syndrome X—those with normal or “near-normal” coronary arteriograms, rest angina, and evidence of myocardial ischaemia. The investigators propose that “microvascular spasm” is the underlying mechanism. Chest pain and ischaemic ECG changes in patients with syndrome X are often indistinguishable from those in patients with coronary-artery disease. However, objective evidence for myocardial ischaemia remains elusive in patients with syndrome X. They do not develop wall-motion abnormalities during stress echocardiography, nitrates improve symptoms in only a proportion of cases, and the long-term prognosis is good in terms of survival. Transient myocardial perfusion abnormalities during stress testing have been observed in patients with chest pain, coronary endothelial dysfunction, and normal or “near-normal” coronary arteriograms. Such perfusion defects, however, may be the result of regional inequalities of myocardial perfusion rather than of ischaemia. Recently, it has also been suggested that thallium perfusion defects in syndrome X may result from non-ischaemic leakage of potassium ions due to abnormal ion-pump function. Reduced myocardial lactate extraction during stress testing, suggesting a possible shift to anaerobic metabolism, has been reported in patients with chest pain and normal coronary arteriograms. However, decreased lactate extraction, as assessed by simultaneous arterial and coronary-sinus measurements, is not a reliable marker of ischaemia because it depends on substrate availability and may be a normal response to stress induced by pacing. Net myocardial lactate production (excess of coronarysinus lactate concentration over arterial concentration) is a more objective marker of ischaemia and has also been reported in syndrome X, albeit in a minority of patients. Metabolic evidence of myocardial ischaemia is found in 10–40% of syndrome X patients, although the prevalence of lactate “producers” varies from 100% in older studies to 0% in more recent ones. In a 1966 paper, over 20% of patients with syndrome X developed myocardial ischaemia as assessed by coronary-sinus pH monitoring during pacing stress. Controversy regarding ischaemia in syndrome X probably stems from the fact that the studies have been small and the study populations usually heterogeneous. Mohri and colleagues contribute to the debate on the pathogenesis of syndrome X. They investigated the response to the administration of intracoronary acetylcholine, a sensitive and specific test for coronaryartery spasm, in 117 chest-pain patients with normal or “minimally diseased” coronary arteries (less than 50% reduction in lumen diameter). Most of the patients had angina at rest, suggestive of coronary spasm. At angiography, 63 patients (54%) had epicardial coronaryartery spasm (more than 75% lumen-diameter reduction from baseline), 29 (25%) had no epicardial coronary spasm despite angina and/or ischaemic ECG changes (“microvascula-spasm” group), and the remainder (21%) had no spasm, angina, or ECG changes (“atypical-chestpain” group). Of importance, nine of 11 patients in the microvascular-spasm group who underwent lactate measurements showed myocardial lactate production, whereas none of the patients with atypical chest pain had metabolic abnormalities despite a similar degree of coronary constriction in both groups. Although the evidence for myocardial ischaemia in at least some of Mohri’s patients seems convincing, an argument commonly used against the presence of ischaemia in patients with syndrome X is the absence of wall-motion abnormalities during stress. Unfortunately, Mohri and colleagues did not assess ventricular function. Nor have many other studies addressed this important issue systematically. Mohri and colleagues speculate that microvascular spasm was the underlying cause because angina, ischaemic ECG changes, and metabolic abnormalities in the microvascular-spasm group occurred in the absence of epicardial coronary spasm or an increase in myocardial oxygen demand. Although it is conceivable that microvascular abnormalities were responsible for the findings, the importance of epicardial coronary constriction in reducing myocardial blood flow should not be underestimated, especially if vasomotor changes are as great as those reported by Mohri and colleagues. COMMENTARY

Serum Endothelin Levels and Pain Perception in Patients With Cardiac Syndrome X and in Healthy Controls

The possible algogenic effects of elevated serum endothelin levels in cardiac syndrome X were investigated in a case-control study that examined somatic pain perception in the forearm during submaximal effort tourniquet and cold immersion tests. Pain threshold to both ischemic and cold stimulation of the forearm was demonstrated to be significantly lower in patients with syndrome X than in matched healthy controls, and a negative correlation between ischemic pain threshold and endothelin levels was demonstrated.

Atheromatous plaque location and arterial remodelling

See doi:10.1016/S1095-668X(02)00426-8for the article to which this editorial refers. Atherosclerosis is associated with a number of structural and functional changes in the arterial wall. Endothelial dysfunction, oxidised-LDL accumulation, increased concentrations of macrophages, neutrophils and T-cells as well as smooth muscle cell migration are some of the most relevant changes that take place during atherogenesis and coronary artery disease progression. It has been shown that the presence of a space-occupying plaque is commonly associated with the expansion of the arterial wall (‘vessel remodelling’).1 The mechanisms responsible for this phenomenon are speculative. The majority of coronary artery atheromatous plaques are eccentric and tend to grow towards the adventitia before encroaching upon the lumen of the artery. This was shown initially by Glagov et al.1 in a pioneering study, which demonstrated thatleft main coronary arteries enlarge in response to atheromatous plaque growth, a phenomenon termed remodelling. Interest in arterial remodelling grew significantly in recent years with the advent of intravascular ultrasound (IVUS) imaging.2,3 Both ‘positive’ and ‘negative’ types of vascular remodelling have been identified. Positive arterial remodelling is described by pathologists as outward plaque bulging associated with the thinning of the arterial media. Positive remodelling is also defined by IVUS as the (positive) ratio: external elastic membrane (EEM) area measured at thelesion site/EEM measured at a control reference site. Negative remodelling, identified in IVUSstudies, describes a ‘paradoxical wall shrinkage’ at the site of atheromatous plaques. This type of remodelling is more commonly found in peripheral arteries compared to coronary arteries.4–6 There is an apparently erratic behaviour of atheromatous coronary artery segments regarding wall expansion at …

Infection, Endothelial Dysfunction, and Atherogenesis

To the Editor: Khairy et al1 reported a lack of association between chronic infection and endothelial function in healthy young men. The study population was highly selective and, excluded women, individuals aged ≥45 years, and subjects with any conventional risk factors of coronary artery disease (CAD). The authors assumed that serum antibodies against the various infectious agents investigated represented evidence of chronic infection. The results of Khairy et al1 are indirectly supported by findings of other authors,2,3 who reported that seropositivity to infectious agents was not associated with increased atherothrombotic risk. However, they contrast with data by Prasad et al,4 who found a significant correlation between total infectious burden to five infectious agents and decreased intracoronary endothelial function. Khairy et al1 suggest that the discrepancies between studies are due to different patient populations, different infectious agents, and different methods of assessing outcome. Moreover, they point out that interactive effects between conventional risk factors and infectious agents could have played a role in …