Christine Espinola-Klein

Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease: Results from the AtheroGene Study

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 &mgr;mol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.

CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels

Monocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-α, and are elevated in various inflammatory diseases.We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-α, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16+ monocytes than controls (13.6% versus 11.4%; p

Genetic Analysis of the Interleukin-18 System Highlights the Role of the Interleukin-18 Gene in Cardiovascular Disease

Background—Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system—IL18, IL18R1, IL18RAP, and IL18BP—in relation to circulating IL-18 levels and cardiovascular mortality. Methods and Results—Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n=142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during ≤4 years of follow-up (HR=2.96, 95% CI 1.54 to 5.70, P=0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels (P=0.002) and cardiovascular mortality (P=0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9% lowering effect on IL-18 levels and a protective effect on risk (HR=0.57, 95% CI 0.36 to 0.92). IL18 haplotypes explained only 2% of IL-18 variability. Adjustment for baseline IL-18 levels abolished the association of haplotypes with cardiovascular risk. The haplotype associated with phenotypes was the only one carrying the minor allele of the IL18/A+183G polymorphism located in the 3′untranslated region and potentially affecting mRNA stability. The other genes of the system were not related to IL-18 levels or cardiovascular outcome. Conclusion—Variations of the IL18 gene consistently influence circulating levels of IL-18 and clinical outcome in patients with coronary artery disease, which supports the hypothesis of a causal role of IL-18 in atherosclerosis and its complications.

Impact of Infectious Burden on Progression of Carotid Atherosclerosis

Background and Purpose— Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. The extent of atherosclerosis and the prognosis of patients with atherosclerosis seem to be increased by the number of infections to which an individual has been exposed. In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the progression of carotid atherosclerosis. Methods— In 504 patients (74.9% men; age, 62.9±10 years), we measured intima-media thickness and prevalence of carotid artery stenosis. Follow-up measurements after a mean of 2.5 years were available in 427 patients (85%). Blood samples were taken, and IgG or IgA antibodies to Chlamydia pneumoniae, Helicobacter pylori, Haemophilus influenzae, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus types 1 and 2 were measured. Statistical evaluation was performed with logistic regression procedures. Results— Elevated IgA antibodies against C pneumoniae (P <0.04) and IgG antibodies against Epstein-Barr virus (P <0.01) and herpes simplex virus type 2 (P <0.04) were associated with progression of atherosclerosis (increase of intima-media thickness ≥0.1 mm/y or progression of carotid stenosis) after adjustment for age, sex, cardiovascular risk factors, highly sensitive C-reactive protein, and statin intake. Infectious burden, divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities, was significantly associated with progression of atherosclerosis, with odds ratios of 1.8 (95% confidence interval, 1.1 to 2.9) for 4 to 5 and 3.8 (95% CI, 1.6 to 8.8) for 6 to 8 compared with 0 to 3 seropositivities after adjustment. Conclusions— Our results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the progression of carotid atherosclerosis.

Different Calculations of Ankle-Brachial Index and Their Impact on Cardiovascular Risk Prediction

Background— An ankle-brachial index (ABI; ratio of ankle and brachial systolic blood pressure) <0.9 indicates peripheral arterial disease (PAD) and is a strong predictor of cardiovascular events. The aim of the present study was to address the prognostic value of different methods of ABI calculation. Methods and Results— In 831 patients admitted with chest pain for diagnostic heart catheterization, blood pressure of both anterior and posterior tibial arteries was measured. ABI was calculated for each leg with the higher of the 2 ankle pressures (current definition of the American Heart Association) or with the lower of the 2 ankle pressures (modified definition) in relation to the higher of the left or right brachial systolic blood pressure. For each patient, the lower ABI from both legs was used for further evaluation. Fifteen patients (1.8%) with ABI >1.5 were excluded. We compared patients with ABI <0.9 according to the current definition (with PAD, n=204 [25.0%]), those with ABI ≥0.9 according to the modified definition (without PAD, n=524 [64.2%]), and those with ABI <0.9 according to the modified definition and ≥0.9 according to the current definition (suspected PAD, n=88 [10.8%]). Follow-up data (median 6.6 years) were available for 812 patients (99.5%); 157 patients (19.3%) experienced cardiovascular events (cardiovascular death, myocardial infarction, or stroke). Patients without PAD had the lowest cardiovascular event rate, whereas event rates were comparable for patients with PAD and those with suspected PAD (14.8% versus 28.4% versus 25.0%, respectively). In a fully adjusted Cox regression analysis that included patients without PAD as the reference group, the hazard ratio (95% CI) was 1.56 (0.97 to 2.53) for patients with suspected PAD and 1.67 (1.16 to 2.40) for patients with PAD. Conclusions— When the higher ankle pressure is used for ABI calculation, a group of patients at high risk for cardiovascular events is overlooked. With a simple modification of ABI (use of the lower instead of the higher ankle pressure), more patients at risk could be identified.

Cytomegalovirus Infection With Interleukin-6 Response Predicts Cardiac Mortality in Patients With Coronary Artery Disease

Background—Prospective data relating previous exposure to cytomegalovirus (CMV) to the risk of cardiac mortality are controversial. We investigated the effect of previous exposure to CMV infection on the risk of future cardiac disease-related death in relation to an underlying inflammatory response. Methods and Results—Coronary angiography was performed in 1134 subjects, and 989 patients with documented coronary artery disease were studied prospectively. CMV-IgG titers and interleukin (IL)-6 levels were measured before angiography. Increasing titers of CMV correlated with the elevation of IL-6 levels (P <0.001) after adjustment for possible confounders. All patients were followed up for a median of 3.1 years (maximum 4.3 years). During follow-up, 96 patients died, 70 of cardiac disease. Overall, CMV seropositivity was not related to cardiac mortality after adjustment for confounding variables (P =0.19). In contrast, in patients with elevated IL-6 levels (≥11.9 pg/mL, median level), CMV seropositivity was independently associated with a 3.2-fold (95% CI 1.4 to 7.3, P =0.007) increase in risk of future cardiac death, whereas in individuals without IL-6 elevation, previous CMV infection had no effect on cardiac mortality. Conclusions—CMV seropositivity in patients with an inflammatory response is independently associated with future cardiac mortality, whereas this association is lost in patients who do not demonstrate an inflammatory response. These data support the hypothesis that the atherosclerotic effects of CMV are mediated through an underlying inflammatory response.

Are Morphological or Functional Changes in the Carotid Artery Wall Associated With Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, or Herpes Simplex Virus Infection?

Background and Purpose Chronic infection with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and herpes simplex virus (HSV) has been implicated in the pathogenesis of atherosclerosis. The carotid intima-media thickness (IMT) can be taken to indicate early atherosclerosis, the presence of a carotid stenosis is a marker of a manifest carotid atherosclerosis, and an increase in arterial stiffness is used as marker of structural and functional changes in an atherosclerotic vessel wall. Methods In 504 patients (75% men; mean age 62.9 [SD 10] years), we measured the IMT and the elastic pressure modulus (EP; n=445) of the common carotid artery and the prevalence of a internal or external carotid artery stenosis. Blood samples were taken, and antibodies against C pneumoniae, H pylori, CMV, and HSV types 1 and 2 were evaluated. Statistical evaluation was performed with regression procedures and multivariate logistic regression analyses. Results Seropositivity for C pneumoniae was an independent predictor for a combined end point of highest category of IMT and carotid artery stenosis (OR 1.8, 95% CI 1.1 to 3.1; adjusted) for IgG titers. Independently, CMV increased the risk for the combined end point (OR 1.7, 95% CI 1.1 to 2.8; adjusted) for IgG titers and for IgA titers (OR 2.3, 95% CI 1.1 to 4.9; adjusted). We found a significant correlation between IgG antibodies against CMV and EP; HSV type 2 IgG titers were associated with IMT and carotid stenosis, but the latter results were no longer significant after adjustment. There was no association with H pylori or HSV type 1. Conclusions We found a significant association of IgG antibodies against C pneumoniae and CMV with early and advanced carotid atherosclerosis. CMV was also correlated to functional changes of the carotid artery, but this could not be confirmed after adjustment.

Influence of HMG–CoA reductase inhibitors on markers of coagulation, systemic inflammation and soluble cell adhesion

BACKGROUND Beneath its lipid-lowering properties additional non-lipid effects of statin therapy are discussed. We therefore examined the impact of statins on laboratory markers of coagulation, inflammation and soluble cell adhesion to further explore these effects in 950 hospitalised patients with angiographically proven CAD. METHODS AND RESULTS Although no significant differences were found in total cholesterol, LDL and HDL and triglyceride levels a statistically lower value in 277 statin-treated patients was found for von Willebrand factor [162(130/224) vs. 208(154/283)%, P=0.0001], leukocyte count [6.9(5.8/8.4) vs. 7.3(6.1/9.4)/nl, P=0.0005], high sensitive CRP [4.3(1.8/10.8) vs. 7.6(2.8/20.0) mg/dl, P=0.0001], interleukin-6 [9.5(5.1/18.7) vs. 14.4(7.2/28.1) mg/dl, P=0.0001] and soluble p-selectin [112.6(82.0/146.0) vs. 127.8(93.8/162.4) mg/dl, P=0.001] compared to 673 patients without statin therapy. This result was confirmed in a subgroup of 510 patients matched for age, gender and percentage of acute coronary syndromes. CONCLUSIONS In statin treated patients significantly lower levels of coagulation, systemic inflammation and soluble cell adhesion markers were found. Therefore the effect of statin therapy may also be mediated by additional non-lipid-lowering effects.

Impact of routine angiographic follow-up after angioplasty

BACKGROUND There is an ongoing controversy as to whether repeat coronary angiography should be routinely performed after successful percutaneous transluminal coronary angioplasty (PTCA). METHODS We examined the 10-year outcome in 400 patients who had or had not undergone an angiographic control 6 months after successful PTCA and a subsequent event-free 6-month period. Our comparison was based on data gathered by questionnaire and telephone interview in 315 patients with (group A) and 85 patients without (group B) a routine 6-month angiographic control. Multivariate analysis (Cox model) was performed to identify predictors of adverse events. RESULTS During the 10-year follow-up period, 22 (7%) of the 315 patients in group A died, compared with 16 (19%) patients in group B (P= .003). In groups A and B, respectively, acute myocardial infarction occurred in 28 (9%) and 10 (12%) patients (not significant [NS]); coronary artery bypass grafting (CABG) was performed in 42 (13%) and 14 (16%) patients (NS); repeat PTCA was performed in 89 (28%) and 11 (13%) patients (P= .012); and serious adverse events (death, myocardial infarction, CABG) occurred in 76 (24%) and 32 (38%) patients (P= .02). Absence of a 6-month angiographic follow-up was identified as an independent predictor of death associated with a 2.7 times higher mortality rate during the 10-year follow-up period. Previous myocardial infarction increased the risk of death 2.5 times. Any increase of residual diameter stenosis by 10% was combined with a 1.4 times higher mortality rate. The chance of bypass surgery was higher in patients with multivessel disease (2.9 times), in patients with unstable angina (2.1 times), and in case of an increase of residual diameter stenosis by 10% (1.3 times). No predictor for the risk of myocardial infarction was found. Angiographic follow-up increased the likelihood of PTCA 2.5 times. CONCLUSIONS A routinely performed angiographic control 6 months after successful PTCA is associated with a significantly higher rate of repeat PTCA but, most important, is correlated with a significantly lower mortality rate during the 10-year follow-up period.

Direct measurement of left ventricular outflow tract by transthoracic real-time 3D-echocardiography increases accuracy in assessment of aortic valve stenosis

BACKGROUND Evaluation of aortic valve stenosis is a major clinical application of echocardiography. The widely employed continuity equation requires determination of the left ventricular outflow tract (LVOT) area. We aimed at testing whether direct area measurement in a volume data set is superior to conventional calculation from the LVOT diameter. METHODS We performed LVOT measurement in 20 normal subjects and 83 patients with moderate to severe aortic stenosis with a transthoracic real-time three-dimensional echocardiography (3D-TTE) technique in two systolic frames. The off-line 3D-evaluation allows full choice of section planes within the acquired volume data set. The aortic valve area was calculated from systolic LVOT areas. These results were compared to area values obtained by M-mode LVOT-diameters (area=pi(*)(d/2)(2)). In addition, the calculated aortic valve orifices were compared to invasive measurements or direct planimetry in the transthoracic or transesophageal examination. RESULTS Two independent observers found a reduction in LVOT area during systole (p<0.001). Often a more ellipsoid-like shaped LVOT resulted at end-systole which was shown by a reduction (p<0.001) of the LVOT longitudinal to oblique axis ratio. 3D-TTE determination of aortic valve orifice areas (mean difference: -0.04+/-0.09 cm(2)) showed a lesser deviation from the invasively or planimetrically measured areas than conventionally calculated LVOT areas (mean difference: -0.1+/-0.1 cm(2)) using the continuity equation (p<0.001). CONCLUSIONS The tested transthoracic 3D-echocardiography technique offers non-invasive measurement of the LVOT and aortic valve area based on the continuity equation during systole and thus improves accuracy and, additionally, agreement of aortic valvular area determination with invasive and direct measurements.