Claus Bartels

Endovascular presence of viable Chlamydia pneumoniae is a common phenomenon in coronary artery disease.

OBJECTIVES We sought to examine coronary arteries for the presence of viable bacteria of the fastidious species Chlamydia pneumoniae. BACKGROUND The respiratory pathogen C. pneumoniae has been implicated in the pathogenesis of coronary artery disease (CAD). Previous studies have demonstrated an antichlamydial seroresponse to be a cardiovascular risk factor and coronary atheromata to contain chlamydial components in varying proportions. Endovascular demonstration of replicating bacteria is required to provide evidence for an infectious component in CAD and a rationale to discuss antimicrobial therapy. METHODS Myocardial revascularization was performed in 70 patients. Atherosclerotic lesions from 53 coronary endarterectomy and 17 restenotic bypass samples were cultured and subjected to nested polymerase chain reaction (PCR) for C. pneumoniae. Antichlamydial immunoglobulin G (IgG), IgA and IgM was examined by microimmunofluorescence. RESULTS Viable C. pneumoniae was recovered from 11 (16%) of 70 atheromata, and chlamydial deoxyribonucleic acid (DNA) was detected in 21 (30%) of 70 atheromata; 17 nonatherosclerotic control samples were PCR-negative (p < 0.01). Fifteen (28%) of 53 endarterectomy and 6 (35%) of 17 bypass samples were PCR-positive. DNA sequencing of six different PCR products did not reveal differences between coronary isolates and respiratory reference strains, suggesting that common respiratory strains gain access to the systemic circulation. Serologic results did not correlate with direct detection results and did not identify individual endovascular infection. CONCLUSIONS A significant proportion of atherosclerotic coronary arteries harbor viable C. pneumoniae. This finding supports the hypothesis of a chlamydial contribution to atherogenesis. Whether chlamydiae initiate atherosclerotic injury, facilitate its progression or colonize atheromata is unknown. However, the endovascular presence of viable bacteria justifies a controlled clinical investigation of antimicrobial treatment benefit in the therapy and prevention of CAD.

Sodium-Hydrogen Exchange Inhibition by Cariporide to Reduce the Risk of Ischemic Cardiac Events in Patients Undergoing Coronary Artery Bypass Grafting: Results of the EXPEDITION Study

BACKGROUND The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size. METHODS High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months. RESULTS At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant. CONCLUSIONS The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.

Local Generation of C-Reactive Protein in Diseased Coronary Artery Venous Bypass Grafts and Normal Vascular Tissue

Background—Venous coronary artery bypass grafts (CABGs) are prone to accelerated atherosclerosis. In atherosclerotic diseases, serum C-reactive protein (CRP) levels have become an important diagnostic and prognostic marker. The origin of CRP in this setting remains to be elucidated. Methods and Results—Monoclonal anti-CRP identified CRP expression in medial and intimal &agr;-actin–positive smooth muscle cells (SMCs) of diseased CABGs with type V and VI lesions and also of native saphenous veins of atherosclerotic individuals. In addition, patent coronary arteries with type IV and V but not with type I through III lesions exhibited intense SMC staining for CRP. Calcified desobliterates of occluded coronary arteries with end-stage disease did not show SMC staining for CRP and were consistently negative for CRP mRNA, as detected by means of real-time polymerase chain reaction. However, CRP mRNA was expressed in 11 of 15 diseased CABGs and also in 10 of 15 native veins. By contrast, only 3 of 18 internal mammary and 4 of 12 radial arteries with virtually no atherosclerosis were positive for CRP mRNA. Conclusions—CRP is produced by SMCs of atherosclerotic lesions with active disease but not in end-stage plaques. The role of CRP constitutively expressed by normal vascular tissue in vein graft disease has yet to be elucidated.

Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release: Results from the GUARDIAN trial

OBJECTIVES We sought to determine if elevated cardiac serum biomarkers after coronary artery bypass graft surgery (CABG) are associated with increased medium-term mortality and to identify patients that may benefit from better postoperative myocardial protection. BACKGROUND The relationship between the magnitude of cardiac serum protein elevation and subsequent mortality after CABG is not well defined, partly because of the lack of large, prospectively studied patient cohorts in whom postoperative elevations of cardiac serum markers have been correlated to medium- and long-term mortality. METHODS The GUARD during Ischemia Against Necrosis (GUARDIAN) study enrolled 2,918 patients assigned to the entry category of CABG and considered as high risk for myocardial necrosis. Creatine kinase-myocardial band (CK-MB) isoenzyme measurements were obtained at baseline and at 8, 12, 16 and 24 h after CABG. RESULTS The unadjusted six-month mortality rates were 3.4%, 5.8%, 7.8% and 20.2% for patients with a postoperative peak CK-MB ratio (peak CK-MB value/upper limits of normal [ULN] for laboratory test) of < 5, > or = 5 to <10, > or =10 to < 20 and > or =20 ULN, respectively (p < 0.0001). The relationship remained statistically significant after adjustment for ejection fraction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, cardiac arrhythmias and the method of cardioplegia delivery. Receiver operating characteristic curve analysis revealed an area under the curve of 0.648 (p < 0.001); the optimal cut-point to predict six-month mortality ranged from 5 to 10 ULN. CONCLUSIONS Progressive elevation of the CK-MB ratio in clinically high-risk patients is associated with significant elevations of medium-term mortality after CABG. Strategies to afford myocardial protection both during CABG and in the postoperative phase may serve to improve the clinical outcome.

Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: Results of the CABG surgery cohort of the GUARDIAN study

OBJECTIVES To evaluate the effects of cariporide on all-cause mortality or myocardial infarction at 36 days in patients at risk of myocardial necrosis after coronary artery bypass graft surgery. METHODS In the coronary artery bypass graft cohort of the GUARD During Ischemia Against Necrosis trial, patients > or =18 years who required urgent coronary artery bypass graft, repeat coronary artery bypass graft, or had a history of unstable angina and > or =2 risk factors (age >65 years, female gender, diabetes mellitus, ejection fraction <35%, or left main or 3-vessel disease) were randomized to placebo (n = 743) or cariporide 20 mg (n = 736), 80 mg (n = 705), or 120 mg (n = 734). A 1-hour intravenous infusion was initiated shortly before surgery and administered every 8 hours for 2 to 7 days. Patients were followed up for 6 months. A nonparametric covariance analysis was used to calculate the primary efficacy endpoint. RESULTS Baseline characteristics were similar between treatment groups. The cariporide 20- and 80-mg groups had event rates similar to placebo. The endpoint of all-cause mortality or myocardial infarction at day 36 was significant with cariporide 120 mg versus placebo (event rate 12.2% vs 16.2%; P =.027). The risk reduction was evident on postoperative day 1 (3.3% vs 6.5%; P =.005) and was maintained at 6 months (event rate 15.0% vs 18.6%; P =.033). Cariporide was well tolerated, and most adverse events were mild and transient in this high-risk population. CONCLUSIONS Clinical benefit with cariporide 120 mg was observed early after treatment initiation and continued for 6 months postsurgery, suggesting that sodium-hydrogen exchange inhibition with cariporide is cardioprotective in patients undergoing high-risk coronary artery bypass graft surgery.

Endovascular presence of Chlamydia pneumoniae DNA is a generalized phenomenon in atherosclerotic vascular disease

The common respiratory pathogen Chlamydia pneumoniae has been implicated in the pathogenesis of coronary artery disease and acute myocardial infarction. In order to verify the endovascular presence of potentially viable chlamydia by detection of genomic DNA, we examined atherosclerotic arteries from various vascular regions using a C. pneumoniae specific nested polymerase chain reaction (PCR). The samples were obtained during surgical revascularization procedures or at autopsy. Chlamydial DNA was detected in 51/238 (21%) atherosclerotic samples. A total of 17 non-atherosclerotic control samples were PCR-negative. Chlamydial presence was detected in 36/140 (26%) vascular samples obtained at coronary revascularization procedures, in 9/61 (15%) samples from carotid artery stenosis, 3/17 (18%) samples from the aorta, and 3/20 (15%) iliac artery samples. Histomorphological discrimination of infected and non-infected arterial samples was not possible. Antichlamydial IgG and IgM response as examined by microimmunofluorescence assay did not aid identification of individual endovascular infection. C. pneumoniae is present in a significant proportion of atherosclerotic arteries. Its occurrence in atheromatous plaques is not limited to coronary arteries and may be considered indicative of an infectious component in atherosclerosis. However, it remains unclear whether chlamydia actually initiates atherosclerotic injury, facilitates its progression, or merely colonizes pre-existing atheromata.

Poor correlation between microimmunofluorescence serology and polymerase chain reaction for detection of vascular Chlamydia pneumoniae infection in coronary artery disease patients

Chlamydia pneumoniae has been associated to coronary artery disease by various methods including recovery of viable bacteria from plaques. The pathogenetical relevance of this is unclear but investigation of antichlamydial therapy in coronary arteriosclerosis is already in progress. The microimmunofluorescence test (MIF), the only species-specific serological assay available, might be considered useful in identifying patients with vascular chlamydial infection. However, this has never been systematically examined. We compared levels of C. pneumoniae antibodies in sera using MIF with direct detection of C. pneumoniae in coronary artery segments from 158 patients undergoing myocardial revascularization. A polymerase chain reaction (PCR) protocol, recently evaluated for use with vascular materials, detected C. pneumoniae infection in 34 patients. Correlation of serology and PCR was poor: in relation to PCR, MIF-IgG analysis had 21% sensitivity, 90% specificity, 37% positive predictive value, and 81% negative predictive value for detection of chlamydial presence. Thus, the MIF test currently appears not suitable to predict individual vascular C. pneumoniae infection.

Detection of Chlamydia pneumoniae But Not Cytomegalovirus in Occluded Saphenous Vein Coronary Artery Bypass Grafts

BACKGROUND A causal relation between atherosclerosis and chronic infection with Chlamydia pneumoniae and/or cytomegalovirus (CMV) has been suggested. Whether the unresolved problem of venous coronary artery bypass graft occlusion is related to infection with C pneumoniae and/or CMV has not been addressed. METHODS AND RESULTS Thirty-eight occluded coronary artery vein grafts and 20 native saphenous veins were examined. Detection of C pneumoniae DNA was performed by use of nested polymerase chain reaction (PCR). Homogenisates from the specimen were cultured for identification of viable C pneumoniae. Both conventional PCR and quantitative PCR for detection of CMV DNA were applied. Differential pathological changes (degree of inflammation, smooth muscle cell proliferation [MIB-1]) were determined and correlated to the detection of both microorganisms. C pneumoniae DNA could be detected in 25% of occluded vein grafts. Viable C pneumoniae was recovered from 16% of occluded vein grafts. Except for 1 native saphenous vein, all control vessels were negative for both C pneumoniae detection and culture. All pathological and control specimens were negative for CMV DNA detection. Pathological changes did not correlate with C pneumoniae detection. CONCLUSIONS Occluded aorto-coronary venous grafts harbor C pneumoniae but not CMV. The detection of C pneumoniae in occluded vein grafts warrants further investigation.

Management of porcelain aorta during coronary artery bypass grafting

BACKGROUND Patients with porcelain aorta carry a high risk of systemic embolism during coronary artery bypass grafting. No currently proposed surgical approach avoids manipulation of the heavily calcified ascending aorta. A novel surgical approach avoiding manipulation of the porcelain aorta was evaluated with regard to its efficacy in prevention of atheroemboli. METHODS The following surgical protocol was performed in 23 patients with porcelain aorta: (1) arterial cannulation of the axillary artery, (2) hypothermic fibrillatory arrest for performance of the distal anastomosis, and (3) construction of the proximal anastomosis to the inominate artery or to a disease-free area of the ascending aorta during hypothermic circulatory arrest. RESULTS The postoperative course was uneventful in all patients. No patient experienced a cerebrovascular accident or visceral organ injury as a result of atheroemboli. CONCLUSIONS The proposed surgical approach is safe and reliable in patients with porcelain aorta and has the potential to reduce the prevalence of stroke and systemic embolization associated with coronary artery bypass grafting in patients with porcelain aorta.

Valve-sparing aortic root replacement (remodeling/reimplantation) in acute type A dissection

BACKGROUND High reoperation rates after supracommissural tube graft replacement for acute type A dissection due to sinus of Valsalva dilation have been reported. Valve-sparing operations focusing on the replacement of the sinus of Valsalva are an appealing alternative. The applicability of these techniques in acute type A dissection remains debatable and results are limited. METHODS From 1992 to 1998, 20 patients with acute type A dissection received a valve-sparing aortic root replacement. Two different types of aortic valve-sparing operations were performed: the remodeling technique in 11 patients and the reimplantation technique in 9 patients. Patients were followed for 26 +/- 18 months. Echocardiographic studies were performed every 6 months. RESULTS There were 2 early postoperative deaths and no late death, no reoperation, and no thromboembolic events. The latest echocardiographic studies of the 18 survivors showed a competent valve in 12 and a trivial aortic valve insufficiency in 6 patients. The mean aortic valve pressure gradient was 4.3 +/- 1.3 mm Hg. CONCLUSIONS These midterm results support the surgical strategy of valve-sparing aortic root replacement in patients with acute type A dissection.