Paul Fefer

Usefulness of Pretreatment With High-Dose Clopidogrel in Patients Undergoing Primary Angioplasty for ST-Elevation Myocardial Infarction

We evaluated the effect and optimal dose of clopidogrel pretreatment in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). The study included 383 consecutive patients with ST-elevation myocardial infarction who had undergone PPCI and were prospectively followed up for a prespecified primary end point of recurrent acute coronary syndrome, stent thrombosis, congestive heart failure, and/or death at 30 days. Of these patients, 217 (57%) received clopidogrel loading before and 166 (43%) after PPCI. A similar number received low (300 mg) and high (600 mg) clopidogrel doses before and after PPCI. Clopidogrel loading before, compared with after, PPCI was associated with a lower incidence of the primary end point (21.7% vs 33.7%, p = 0.008). Clopidogrel pretreatment remained a significant predictor of the primary outcome after adjusting for potential confounders (odds ratio 0.54, 95% confidence interval 0.42 to 0.91). When patients were further stratified into 4 groups according to the timing and dosage of clopidogrel loading, the incidence of the primary outcome was 16% and 27% in those receiving 600 and 300 mg before and 28% and 39% in those receiving 600 and 300 mg after PPCI, respectively (p for trend <0.01). In conclusion, both the timing and the dosage of clopidogrel loading are important and affect the outcome in patients with ST-elevation myocardial infarction undergoing PPCI.

The role of oxidized phospholipids, lipoprotein (a) and biomarkers of oxidized lipoproteins in chronically occluded coronary arteries in sudden cardiac death and following successful percutaneous revascularization

AIMSnOxPL are pro-inflammatory and may mediate atherogenesis, thrombosis and endothelial dysfunction. We studied the histological presence and temporal increases in oxidized phospholipids on apolipoprotein B-100 particles (OxPL/apoB), lipoprotein (a) [Lp(a)] and biomarkers of oxidized lipoproteins in subjects with chronic total coronary occlusions (CTO) with sudden cardiac death (SCD) and following percutaneous coronary intervention (PCI).nnnMETHODSnEight subjects with SCD and CTO and 33 patients with successful PCI of CTO were included. Blood samples were drawn before PCI, immediately post-PCI, at 6 and 24 h, at 3 days and at 1 week. Plasma levels of OxPL/apoB, Lp(a), IgG and IgM autoantibodies to malondialdehyde (MDA) low-density lipoprotein and apoB-immune complexes were measured in all samples and compared with previous data from 141 patients undergoing PCI of non-CTO vessels.nnnRESULTSnImmunohistochemistry of coronary CTOs revealed OxPL and MDA-like epitopes, particularly in areas of recanalized and organized thrombus and neovascularization. Following PCI, OxPL/apoB and Lp(a) levels, expressed as percent change from baseline levels before PCI, rose gradually and progressively over the next 7 days. In contrast, levels of OxPL/apoB and Lp(a) in non-CTO vessels rose immediately post PCI and then dropped rapidly to baseline within 24 h.nnnCONCLUSIONSnCTOs contain immunohistological evidence of OxPL and MDA-like epitopes. Successful PCI of CTOs results in a slower increase in OxPL/apoB and Lp(a) but higher increase in IgM immune complexes compared to non-CTO vessels. Pro-inflammatory oxidation-specific epitopes may impact development of CTOs and affect outcomes following PCI that can be evaluated in larger clinical trials.

Construction of 3D MR image-based computer models of pathologic hearts, augmented with histology and optical fluorescence imaging to characterize action potential propagation

Cardiac computer models can help us understand and predict the propagation of excitation waves (i.e., action potential, AP) in healthy and pathologic hearts. Our broad aim is to develop accurate 3D MR image-based computer models of electrophysiology in large hearts (translatable to clinical applications) and to validate them experimentally. The specific goals of this paper were to match models with maps of the propagation of optical AP on the epicardial surface using large porcine hearts with scars, estimating several parameters relevant to macroscopic reaction-diffusion electrophysiological models. We used voltage-sensitive dyes to image AP in large porcine hearts with scars (three specimens had chronic myocardial infarct, and three had radiofrequency RF acute scars). We first analyzed the main AP waves characteristics: duration (APD) and propagation under controlled pacing locations and frequencies as recorded from 2D optical images. We further built 3D MR image-based computer models that have information derived from the optical measures, as well as morphologic MRI data (i.e., myocardial anatomy, fiber directions and scar definition). The scar morphology from MR images was validated against corresponding whole-mount histology. We also compared the measured 3D isochronal maps of depolarization to simulated isochrones (the latter replicating precisely the experimental conditions), performing model customization and 3D volumetric adjustments of the local conductivity. Our results demonstrated that mean APD in the border zone (BZ) of the infarct scars was reduced by ~13% (compared to ~318 ms measured in normal zone, NZ), but APD did not change significantly in the thin BZ of the ablation scars. A generic value for velocity ratio (1:2.7) in healthy myocardial tissue was derived from measured values of transverse and longitudinal conduction velocities relative to fibers direction (22 cm/s and 60 cm/s, respectively). The model customization and 3D volumetric adjustment reduced the differences between measurements and simulations; for example, from one pacing location, the adjustment reduced the absolute error in local depolarization times by a factor of 5 (i.e., from 58 ms to 11 ms) in the infarcted heart, and by a factor of 6 (i.e., from 60 ms to 9 ms) in the heart with the RF scar. Moreover, the sensitivity of adjusted conductivity maps to different pacing locations was tested, and the errors in activation times were found to be of approximately 10-12 ms independent of pacing location used to adjust model parameters, suggesting that any location can be used for model predictions.

Statin therapy prevents expansive remodeling in venous bypass grafts

BACKGROUNDnVenous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes.nnnMETHODS AND RESULTSnReversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 ± 4.2 mmol/L versus control 38.7 ± 10.6 mmol/L, p<0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 ± 6.6 mm(2) versus control 77.6 ± 10.7 mm(2), p<0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 ± 2.19 mm(2) versus control 9.57 ± 2.43 mm(2), p<0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group.nnnCONCLUSIONnAtorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.

Intraplaque therapies for facilitating percutaneous recanalization of chronic total occlusions.

Chronic total occlusions (CTOs) are found in up to 30% of angiograms performed on patients with coronary disease. The technical difficulty of performing percutaneous coronary interventions (PCIs) in CTOs, primarily because of the inability to cross CTOs with a guide wire, is reflected in low rates of PCI for CTo (approximately 9% of PCI procedures). The main barrier to successful CTO crossing is the dense collagenous extracellular matrix, particularly at the entrance, known as the proximal fibrous cap. Current interventional strategies to overcome this barrier are based primarily on forceful penetration of the CTO plaque by the use of dedicated CTO guide wires. These extra-stiff wires are designed to transfer maximal force to the tip to create a path within the plaque. However, these wires can also cause vascular complications such as dissections; overall procedural success rates remain modest. Several groups are working on new approaches to actually alter the biology and structural characteristics of the CTO plaque to facilitate guide wire crossing. Preliminary data suggest that plaque-directed therapies aimed at priming it for wire crossing may increase PCI success in these challenging cases. New techniques for plaque modification, either by softening the collagenous matrix (collagenase) or by exposing and enlarging existing microvessels (intravascular thrombolysis, contrast injection) or by inducing new microvessels (angiogenic growth factor[s]) are described in the present review.

Characterization of Post-infarct Scars in a Porcine Model --- A Combined Experimental and Theoretical Study

Arrhythmias are often associated with healing infarcts and could arise from the border zone of the scars. The main purpose of this work was to characterize the infarct scars using in vivo electro-anatomic CARTO maps (recorded in sinus rhythm) and high-resolution ex-vivo MR images in a porcine model of chronic infarct. The MR images were segmented into scar, peri-infarct and healthy ventricular tissue, and, in select slices, the results of segmentation were validated against histology. Further, the segmented volumes and associated fiber directions (derived from diffusion-weighted (DW) MRI as well as from synthetic models), were used as input to a simple two-variable mathematical model that calculates the propagation of depolarization waves and isochronal maps; and these isochronal maps were compared to the measured ones. We further correlated the size of the scar measured during the electrophysiology (EP) study with scar dimensions obtained from MRI using ex-vivo DW-MRI methods. Finally, we present preliminary results from a qualitative comparison between the scar delineation from ex vivo and in vivo MR images.

A first-in-man study of percutaneous myocardial cryotreatment in nonrevascularizable patients with refractory angina†‡

Objectives: To evaluate the safety and feasibility of myocardial cryotreatment for patients with coronary artery disease (CAD) and severe angina refractory to standard treatment. Background: Innovative myocardial revascularization strategies are needed for patients with CAD and severe angina uncontrolled by conventional methods. Preclinical data have demonstrated that cryotherapy can induce myocardial neovascularization through arteriogenesis. Methods: This was a two center, nonrandomized, study that enrolled 20 patients. All patients had CAD and severe angina (CCS Angina Class III or IV). Safety was the primary endpoint. Treatment involved 8–10 intramyocardial cryoapplications (at ≤−50°C), for 2 min by a specially designed percutaneous catheter at an identified ischemic area of the myocardium. Primary endpoint was safety, with secondary endpoints of angina severity, exercise tolerance, quality of life, and myocardial perfusion assessed by radionuclide scintigraphy. Results: The procedure was successful in 19 patients. There were three device‐related events, a pericardial tamponade requiring pericardiocenetesis, a clinically nonsignificant pericardial effusion, and an episode of ventricular tachycardia requiring cardioversion in one patient. Complete 12‐month follow‐up was obtained in 16 patients. Significant reduction in CCS angina scores and significant improvements in both exercise tolerance and quality of life (P < 0.05) were seen at 6 and 12‐month follow‐up. Although no significant differences were observed in myocardial perfusion in the overall group, marked improvement was detected in 8 (42%) patients. Conclusion: Cryotreatment is feasible and safe in patients with severe angina refractory to standard management. Early efficacy results are encouraging and further clinical study is warranted.

Impact of successful and failed revascularization of chronic total occlusion on left ventricular function and infarct size

Introduction Non-randomised studies have reported a prognostic advantage with percutaneous coronary intervention (PCI) in the treatment of chronic total occlusions (CTO). Failure to cross and successfully open a CTO confers a worse clinical outcome, however most trials have included occlusions of short duration (7-30 days). PCI success rates are inversely related to the age of vessel occlusion reflecting temporal, cellular changes within a CTO, namely progressive collagen deposition.