Christophe A. Wyss

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.

Characterization of Dysfunctional Myocardium by Positron Emission Tomography and Magnetic Resonance Relation to Functional Outcome After Revascularization

Background—Metabolic assessment of dysfunctional myocardium by PET allows prediction of functional recovery after revascularization. Contrast-enhanced MR (ce-MR) discriminates transmural distribution of viable and scar tissue with excellent spatial resolution. Both techniques were applied in ischemic chronic left ventricular dysfunction to relate metabolism and tissue composition to changes of contractile function after revascularization. Methods and Results—Nineteen patients with myocardial infarctions (>3 months) were studied by MR and PET, and 10 patients were followed by MR 11±2 months after revascularization. In 56 to 64 segments/heart, systolic wall thickening, viable mass, and thickness of viable rim tissue were determined by MR (inversion-recovery MR with 0.25 mmol/kg Gd-chelate). [18F]Fluorodeoxyglucose (FDG) uptake and resting perfusion (13N-ammonia) were determined by PET. Viable tissue per segment on ce-MR correlated with FDG uptake per segment (r =0.62 and 0.82 for segments with and without flow metabolism mismatch, P <0.0001). FDG uptake ≥50% (a predictor of functional recovery) corresponded to a viable rim thickness of 4.5 mm on ce-MR. Thick (>4.5 mm) and metabolically viable segments (≥50% FDG uptake) showed functional recovery in 85%, whereas thin metabolically nonviable segments improved function in 13% (P <0.0005). Metabolically viable segments with a thin viable rim and thick segments with reduced FDG uptake improved function in only 36% and 23% of segments, respectively (NS versus thin metabolically nonviable). In these 2 classes of segments, scar per segment was higher than in thick viable segments (P <0.0001). Conclusions—Metabolism and tissue composition discriminate various classes of dysfunctional myocardium. Most metabolically viable segments with a thick viable rim on ce-MR recover function after revascularization, whereas all other classes showed low recovery rates of contractile function.

Adenosine stress high-pitch 128-slice dual-source myocardial computed tomography perfusion for imaging of reversible myocardial ischemia: comparison with magnetic resonance imaging.

Background— Coronary computed tomography angiography (CTA) enables accurate anatomic evaluation of coronary artery stenosis but lacks information about hemodynamic significance. The aim of this study was to evaluate 128-slice myocardial CT perfusion (CTP) imaging with adenosine stress using a high-pitch mode, in comparison with cardiac MRI (CMR). Methods and Results— Thirty-nine patients with intermediate to high coronary risk profile underwent adenosine stress 128-slice dual source CTP (128×0.6 mm, 0.28 seconds). Among those, 30 patients (64±10 years, 6% women) also underwent adenosine stress CMR (1.5T). The 2-step CTP protocol consisted of (1) adenosine stress-CTP using a high-pitch factor (3.4) ECG-synchronized spiral mode and (2) rest-CTP/coronary-CTA using either high-pitch (heart rate <63 bpm) or prospective ECG-triggering (heart rate >63 bpm). Results were compared with CMR and with invasive angiography in 25 patients. The performance of stress-CTP for detection of myocardial perfusion defects compared with CMR was sensitivity, 96%; specificity, 88%; positive predictive value (PPV), 93%; negative predictive value (NPV), 94% (per vessel); and sensitivity, 78%; specificity, 87%; PPV, 83%; NPV, 84% (per segment). The accuracy of stress-CTP for imaging of reversible ischemia compared with CMR was sensitivity, 95%; specificity, 96%; PPV, 95%; and NPV, 96% (per vessel). In 25 patients who underwent invasive angiography, the accuracy of CTA for detection of stenosis >70% was (per segment): sensitivity, 96%; specificity, 88%; PPV, 67%; and NPV, 98.9%. The accuracy improved from 84% to 95% after adding stress CTP to CTA. Radiation exposure of the entire stress/rest CT protocol was only 2.5 mSv. Conclusions— Adenosine-induced stress 128-slice dual-source high-pitch myocardial CTP allows for simultaneously assessment of reversible myocardial ischemia and coronary stenosis, with good diagnostic accuracy as compared with CMR and invasive angiography, at a very low radiation exposure.

Accuracy of low-dose computed tomography coronary angiography using prospective electrocardiogram-triggering: first clinical experience

AIMS To evaluate the accuracy of low-dose computed tomography coronary angiography (CTCA) using prospective ECG-triggering for the assessment of coronary artery disease (CAD). METHODS AND RESULTS A total of 30 patients (19 males, 11 females, mean age 58.8 +/- 9.9 years) underwent low-dose CTCA and invasive coronary angiography (CA) [median 2 days (0, 41)]. Before CT scanning, intravenous beta-blocker was administered in 18 of 30 patients as heart rate (HR) was >65 b.p.m., achieving a mean HR of 55.7 +/- 7.9 b.p.m. CAD was defined as coronary artery narrowing > or =50%, using CA as standard of reference. The estimated mean effective radiation dose was 2.1 +/- 0.7 mSv (range: 1.0-3.3), yielding 96.0% (383/399) of evaluable segments. On an intention-to-diagnose-base, all non-evaluative segments were included in the analysis. Vessels with a non-evaluative segment and no further finding were censored as false positive. Patient-based analysis revealed sensitivity, specificity, positive predictive value, and negative predictive value of 100, 83.3, 90.0, and 100%, respectively. The respective values per vessel were 100, 88.9, 85.7, and 100%, respectively. CONCLUSION Prospective ECG-triggering allows low-dose CTCA and provides high diagnostic accuracy in the assessment of CAD in patients with stable sinus rhythm and a low heart rate.

Intracoronary Injection of Bone Marrow–Derived Mononuclear Cells Early or Late After Acute Myocardial Infarction Effects on Global Left Ventricular Function

Background— Intracoronary administration of autologous bone marrow–derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. Methods and Results— In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (ie, 5 to 7 days) or late (ie, 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was −0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, −1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, −2.61 to 3.71; P=0.73) for the late therapy group. Conclusions— Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Diagnostic Value of 13N-Ammonia Myocardial Perfusion PET: Added Value of Myocardial Flow Reserve

The ability to obtain quantitative values of flow and myocardial flow reserve (MFR) has been perceived as an important advantage of PET over conventional nuclear myocardial perfusion imaging (MPI). We evaluated the added diagnostic value of MFR over MPI alone as assessed with 13N-ammonia and PET/CT to predict angiographic coronary artery disease (CAD). Methods: Seventy-three patients underwent 1-d adenosine stress–rest 13N-ammonia PET/CT MPI, and MFR was calculated. The added value of MFR as an adjunct to MPI for predicting CAD (luminal narrowing ≥ 50%) was evaluated using invasive coronary angiography as a standard of reference. Results: Per patient, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MPI for detecting significant CAD were 79%, 80%, 91%, 59%, and 79%, respectively. Adding a cutoff of less than 2.0 for global MFR to MPI findings improved the values to 96% (P < 0.005), 80%, 93%, 89% (P < 0.005), and 92% (P < 0.005), respectively. Conclusion: The quantification of MFR in 13N-ammonia PET/CT MPI provides a substantial added diagnostic value for detection of CAD. Particularly in patients with normal MPI results, quantification of MFR helps to unmask clinically significant CAD.

First head-to-head comparison of effective radiation dose from low-dose 64-slice CT with prospective ECG-triggering versus invasive coronary angiography

Background: Reduction of radiation burden of multidetector computed tomography coronary angiography (CTCA) has remained an important task. Objective: To compare effective radiation dose of low-dose 64-slice CTCA using prospective ECG-triggering versus diagnostic invasive coronary angiography (CA). Methods: 42 patients referred for elective invasive CA owing to suspected coronary artery disease (CAD) were prospectively enrolled to undergo a low-dose CTCA without calcium scoring within the same day before CA. Dose-area product of diagnostic invasive CA and dose-length product of CTCA were measured, converted into effective radiation dose and compared using Mann-Whitney U tests. In addition, accuracy of CTCA to detect CAD (coronary artery narrowing ⩾50%) was assessed using invasive CA as standard of reference. On an intention-to-diagnose basis all non-evaluative vessels were included in the analysis and censored as positive. Results: The estimated mean effective radiation dose was 8.5 (4.4) mSv (range 1.4–20.5 mSv) for diagnostic invasive CA, and 2.1 (0.7) mSv (range 1.0–3.3 mSv) for CTCA (p<0.001). 19 patients (42.9%) had no CAD by invasive CA. 40 (95.2%) patients have been correctly classified as having CAD (23/23) or no CAD (17/19). Over 97% (551/567) of segments were evaluable. Vessel-based analysis revealed sensitivity, specificity, positive and negative predictive value of 94.2% (CI 0.8% to 1.0%), 94.8% (CI 09% to 1.0%), 89.0% (CI 0.8% to 1.0%), 97.4% (CI 09% to 1.0%) and an accuracy of 94.6%. Conclusions: Low dose CTCA allows evaluation of CAD with high accuracy, but delivers a significantly less effective radiation dose to patients compared to diagnostic invasive CA.

Influence of Altitude Exposure on Coronary Flow Reserve

Background—Although no data exist on the effect of altitude exposure on coronary flow reserve (CFR), patients with coronary artery disease (CAD) are advised not to exceed moderate altitudes of ≈2500 m above sea level. We studied the influence of altitude on myocardial blood flow (MBF) in controls and CAD patients. Methods and Results—In 10 healthy controls and 8 patients with CAD, MBF was measured by positron emission tomography and 15O-labeled water at rest, during adenosine stress, and after supine bicycle exercise. This protocol was repeated during inhalation of a hypoxic gas mixture corresponding to an altitude of 4500 m (controls) and 2500 m (CAD). Workload was targeted to comparable heart rate–blood pressure products at normoxia and hypoxia. Resting MBF increased significantly in controls at 4500 m (+24%, P <0.01) and in CAD patients at 2500 m (+24%, P <0.05). Altitude had no influence on adenosine-induced hyperemia and CFR. Exercise-induced hyperemia increased significantly in controls (+38%, P <0.01) at 4500 m (despite a reduction in workload, −28%, P <0.0001) but not in CAD patients at 2500 m (moderate decrease in workload, −11%, P <0.05). Exercise-induced reserve was preserved in controls (+10%, P =NS) but decreased in CAD patients (−18%, P <0.005). Conclusions—At 2500 m altitude, there is a significant decrease in exercise-induced reserve in CAD patients, indicating that compensatory mechanisms might be exhausted even at moderate altitudes, whereas healthy controls have preserved reserve up to 4500 m. Thus, patients with CAD and impaired CFR should be cautious when performing physical exercise even at moderate altitude.

Diagnostic accuracy of computed tomography coronary angiography and evaluation of stress-only single-photon emission computed tomography/computed tomography hybrid imaging : comparison of prospective electrocardiogram-triggering vs. retrospective gating

AIMS To determine diagnostic accuracy, effective radiation dose, and potential value of computed tomography coronary angiography (CTCA) for hybrid imaging with single-photon emission computed tomography (SPECT) comparing prospective electrocardiogram (ECG)-triggering vs. retrospective ECG-gating. METHODS AND RESULTS Two hundred patients underwent standard myocardial stress/rest- SPECT perfusion imaging, which served as standard of reference. One hundred consecutive patients underwent 64-slice CTCA using prospective ECG-gating, and were compared with 100 patients who had previously undergone CTCA using retrospective ECG-gating. For predicting ischaemia, CTCA with prospective ECG-triggering and a stenosis cut-off >50% had a per-vessel sensitivity, specificity, negative, and positive predictive value of 100, 84, 100, and 30%; respective values for CTCA with retrospective ECG-gating were similar (P = n.s.): 86, 83, 98, and 33%. Combining CTCA with stress-only SPECT revealed 100% clinical agreement with regard to perfusion defects, and provided additional information in half the patients on preclinical coronary findings. Effective radiation dose was 2.2 +/- 0.7 mSv for CTCA with prospective ECG-triggering, and 19.7 +/- 4.2 mSv with retrospective ECG-gating (P < 0.001) (5.4 +/- 0.8 vs. 24.1 +/- 4.3 mSv for hybrid imaging). CONCLUSION Prospective ECG-triggering for CTCA reduces radiation dose by almost 90% without affecting diagnostic performance. Combined imaging with stress-only SPECT is an attractive alternative to standard stress/rest-SPECT for evaluation of coronary artery disease, offering additional information on preclinical atherosclerosis.

Cellular actors, Toll-like receptors, and local cytokine profile in acute coronary syndromes

AIMS Inflammation plays a key role in acute coronary syndromes (ACS). Toll-like receptors (TLR) on leucocytes mediate inflammation and immune responses. We characterized leucocytes and TLR expression within coronary thrombi and compared cytokine levels from the site of coronary occlusion with aortic blood (AB) in ACS patients. METHODS AND RESULTS In 18 ACS patients, thrombi were collected by aspiration during primary percutaneous coronary intervention. Thrombi and AB from these patients as well as AB from 10 age-matched controls without coronary artery disease were assessed by FACS analysis for cellular distribution and TLR expression. For further discrimination of ACS specificity, seven non-coronary intravascular thrombi and eight thrombi generated in vitro were analysed. In 17 additional patients, cytokine levels were determined in blood samples from the site of coronary occlusion under distal occlusion and compared with AB. In coronary thrombi from ACS, the percentage of monocytes related to the total leucocyte count was greater than in AB (47 vs. 20%, P = 0.0002). In thrombi, TLR-4 and TLR-2 were overexpressed on CD14-labelled monocytes, and TLR-2 was increased on CD66b-labelled granulocytes, in comparison with leucocytes in AB. In contrast, in vitro and non-coronary thrombi exhibited no overexpression of TLR-4. Local blood samples taken under distal occlusion revealed elevated concentrations of chemokines (IL-8, MCP-1, eotaxin, MIP-1alpha, and IP-10) and cytokines (IL-1ra, IL-6, IL-7, IL-12, IL-17, IFN-alpha, and granulocyte-macrophage colony-stimulating factor) regulating both innate and adaptive immunity (all P < 0.05). CONCLUSION In ACS patients, monocytes accumulate within thrombi and specifically overexpress TLR-4. Together with the local expression patterns of chemokines and cytokines, the increase of TLR-4 reflects a concerted activation of this inflammatory pathway at the site of coronary occlusion in ACS.