M. Zimarino

Does optical coherence tomography identify arterial healing after stenting? An in vivo comparison with histology, in a rabbit carotid model

Objective: To verify whether optical coherence tomography (OCT) can accurately monitor the occurrence of arterial healing after stenting. Setting: Delayed stent endothelialisation may predispose to stent thrombosis. OCT is a high-resolution intravascular imaging technique that accurately identifies stent struts and arterial tissues. Design and interventions: Eight New Zealand white rabbits underwent the implantation of single bare metal stents (diameter 2–2.5 mm, length 8–13 mm) in the right common carotid artery through the external carotid artery. After a median of 11 days (range 2–28), the stented arteries were visualised by OCT, with images acquired at a pull-back speed of 0.5 mm/sec. The rabbits were then euthanised, vessels were formalin-fixed and finally processed for histopathology. Results: We analysed 32 cross-sections from eight stented carotid arteries, for a total of 384 stent struts. OCT detected all of the stent struts in 30 of 32 cross-sections (93.7%), and correctly identified the presence/absence of tissue for every strut. Histological and OCT measurements of mean neointima thickness (0.135 (SD 0.079) mm and 0.145 (SD 0.085) mm, respectively, pu200a=u200aNS) were similar and closely related (ru200a=u200a0.85, p<0.001). Neointima area progressively increased with longer time intervals from stent deployment to sacrifice; histological and OCT measurements were similar for each time interval. The intra-observer and interobserver reproducibility of OCT neointima measurements were excellent (R2u200a=u200a0.90 and 0.88, respectively). Conclusions: OCT is a promising means for monitoring stent strut coverage and vessel wall healing in vivo, the relevance of which will become even more significant with the increasing use of drug-eluting stents.

The dynamics of the coronary collateral circulation

Coronary collaterals are present at birth, with wide interindividual variation in their functional capacity. These vessels protect jeopardized myocardium, and the number of collaterals and the extent of their coverage are associated with improved survival in patients with coronary heart disease. The collateral circulation is not a permanent set of structures, but undergoes dynamic changes with important consequences for cardioprotection. If a severe atherosclerotic lesion develops in an artery supplying tissue downstream of a total occlusion through collateral blood flow, pressure gradients across the collateral bed change. The result is that some of the collateral flow previously supplying the perfusion territory of the totally occluded artery is redirected to the perfusion territory of the donor artery, thus producing a collateral steal. The collateral circulation can regress once antegrade flow in the main dependent artery is re-established, as occurs following the recanalization of a chronic total occlusion. The clinical benefits of coronary revascularization must be cautiously weighed against the risk of reducing the protective support derived from coronary collaterals. Consequently, pharmacological, gene-based, and cell-based therapeutic attempts have been made to enhance collateral function. Although such approaches have so far yielded no, or modest, beneficial results, the rapidly accruing data on coronary collateral circulation will hopefully lead to new effective therapeutic strategies.

Multislice Spiral Computed Tomography for In-Stent Restenosis

A 72-year-old man was admitted for recurrent episodes of chest pain 3 months after stent deployment in the left anterior descending (LAD) artery. The patient underwent a computerized tomographic (CT) examination of the thorax with a multislice spiral CT scanner (MSCT) (Somatom Volume Zoom, Siemens). A dynamic study was performed with acquisition of 20 scans at the level of the LAD distal to the stented segment during injection of 20 mL of nonionic contrast medium (370 mgI/mL); the resultant time-density curves were suggestive of high-grade stenosis (Figure 1A). Thereafter, a …

The adequacy of myocardial revascularization in patients with multivessel coronary artery disease.

In patients with multi-vessel coronary artery disease (MVCAD) myocardial revascularization may be accomplished either on all diseased lesions--complete myocardial revascularization--or on selectively targeted coronary segments by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Complete revascularization has a potential long-term prognostic benefit, but is more complex and may increase in-hospital events when compared with incomplete revascularization. No conclusive agreement has been yet reached on the optimal extent of revascularization, and guidelines have only recently mentioned the adequacy of revascularization in the decision whether to submit a patient to CABG or PCI. In the absence of any trial specifically designed to assess the relative benefit of either strategy, the present review explores current concepts about the completeness of revascularization, the growing evidence on the relevance of lesion and myocardial functional evaluation, and analyzes currently available data in relation to different clinical settings, including acute coronary syndromes, diabetes, chronic kidney disease and impaired left ventricular function. Considerations on the adequacy of revascularization should guide the choice among PCI and CABG in patients with MVCAD during the decision-making process, taking into account the clinical presentation, the extent and relevance of ischemia and the presence of other comorbidities.

Mechanisms of nitrate tolerance: potential roles of folate.

More than 100 years since their introduction in cardiovascular therapy, nitrates continue to be widely used in ischaemic heart disease despite incomplete knowledge of their intimate mechanism of action. Particularly, the development of a progressive attenuation of their efficacy over prolonged use (tolerance) continues to be the subject of current investigation. Newer findings point to the role of increased intracellular oxidative stress as a mechanism for tolerance and to folic acid derivatives as pharmacologic means to attenuate its development. This paper reviews nitrate mechanism of action, the history of nitrate tolerance and newer findings related to the use of folate to prevent this phenomenon.

Understanding the complexity of abciximab-related thrombocytopenia.

Patients with a rare bleeding disorder characterised by skin and mucosal bleeding – typical of thrombocytopenia – but with a normal platelet count, and later characterised by a defective aggregation to all agonists, described as Glanzmann thrombasthenia, have mutations in a platelet membrane glycoprotein (GP) called GP IIb/IIIa, also known as the integrin αIIbβ3 (1). Such discovery paved the road to a molecular understanding of how platelets aggregate, with GPIIb/IIIa acting as a main ligand for fibrinogen, which in turn provides the main molecular bridge between two adjacent platelets. This was the basis, now more than 15 years ago, for starting the development of a new class of antiplatelet agents directed against GP IIb/IIIa, blocking the final common pathway of platelet aggregation. The first such drug was derived from a murine monoclonal antibody (7E3) recognising activated, but not resting platelets, and binding to an epitope on the GPIIb/IIIa complex close to a critical binding site for fibrinogen (2). To decrease the immunogenicity of the antibody, the pharmaceutical abciximab (ReoPro, developed by Centocor and Eli Lilly), was produced. Abciximab is a chimeric (human/mouse) Fab fragment derived from 7E3, where the N-terminal sequences that control its specificity were incorporated into a human IgG1 framework. The intact chimeric IgG molecule was then cleaved by papain to produce the Fab fragment abciximab. Abciximab is therefore a Fab chimera that retains the mouse-derived variable portion of murine 7E3 joined to the constant region of human IgG Fab. Out of several other molecules developed for intravenous and oral use to target GP IIb/IIIa, two other compounds of this class have become available for intravenous use only. One is the Lys-Gly-Asp (KGD)containing cyclic heptapeptide eptifibatide (Integrilin, developed by ScheringPlough), derived from disintegrins, a class of proteins found in snake venoms and interfering with the binding of Arg-Gly-Asp (RGD)-containing adhesive proteins to cellular integrins. The other is tirofiban (Aggrastat, developed by Merck), developed by engineered synthesis to mimic the charge and spatial conformation of the RGD sequence. These compounds, which are small molecules not per se immunogenic, are collectively termed ligand-mimetic. Abciximab, eptifibatide and tirofiban are currently approved and recommended for therapeutic use in acute coronary syndromes (both ST-elevation myocardial infarction and non-ST elevation acute coronary syndromes), especially in the setting of percutaneous coronary interventions (PCI) (3, 4). Here, in patients with complex anatomy and receiving coronary stents, in the highly thrombogenic setting of acute coronary syndromes, abciximab is currently, within the category, the agent of choice when given at the time of PCI, having shown superiority in one face-to-face trial against tirofiban (5). In earlier clinical trials (6, 7) and in immediate post-marketing surveillance of abciximab, it was found that about 1% of patients develop thrombocytopenia. Thrombocytopenia (nadir platelet count <100x109 cells/l) developed actually in 2.4% of patients treated with abciximab and 0.5% of those treated with tirofiban (p<0.001) in a large series of patients undergoing coronary stenting in the setting of the TARGET study. Here abciximab use was independently associated with the risk of thrombocytopenia Correspondence to: Raffaele De Caterina, MD, PhD Institute of Cardiology and Center of Excellence on Aging “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata Via dei Vestini, 66013 Chieti, Italy Tel.: +39 0871 41512, Fax: +39 0871 402817 E-mail: rdecater@unich.it

Drug-eluting balloons for percutaneous coronary interventions

Correspondence to: Marco Zimarino, MD, PhD Institute of Cardiology “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata Via dei Vestini, 66013 Chieti, Italy Tel: +39 0871 41512, Fax: +39 0871 402817 E-mail: m.zimarino@unich.it Received: November 27, 2008 Accepted: November 27, 2008 Prepublished online: December 4, 2008 doi:10.1160/TH08-11-0770

Response to “Pharmacodynamic Interaction Between Aspirin and Ibuprofen: A Plausible Mechanism of Aspirin Resistance”

To the Editor: We have read with great interest the recent publication by Renda et al. ‘‘Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease’’ describing an interaction between aspirin and ibuprofen undermining the aspirin-related inhibition of platelet cyclooxygenase (COX)-1 activity. Recently, information became available on interference of the cardioprotective effect of aspirin by simultaneous use of ibuprofen. Aspirin binds irreversibly to COX in platelets by binding to serine residue 529. The non-selective non-steroidal anti-inflammatory drugs (for instance ibuprofen) bind reversibly to the active site of COX-1 instead of aspirin. The potential for an interaction between aspirin and non-selective non-steroidal anti-inflammatory drugs therefore exists with the cardioprotective effects of aspirin potentially being blunted by coadministration of non-steroidal antiinflammatory drugs. Indeed, in shortterm ex vivo studies, an interaction between aspirin and ibuprofen was shown to have an effect on platelet function. Moreover, the Tayside study showed a both statistically and clinically significant increased risk of mortality in users of aspirin plus ibuprofen compared with users of aspirin alone. The antiplatelet effect of aspirin is not absolute in all patients, and some patients experience thromboembolic events despite aspirin. These patients are clinically called aspirin-resistant or aspirin non-responders. A prevalence of 5.5–45% in patients with various cardiovascular diseases has been reported for aspirin resistance by different laboratory methods. Proposed mechanisms include non-compliance, inadequate dosing, cigarette smoking, or inappropriate absorption of aspirin. Another suggested mechanism of aspirin resistance is genetic polymorphisms, for instance affecting Ser529 of COX-1 causing ongoing COX-1 activity up to 86% of normal despite aspirin therapy. Moreover, GP IIIa, GP Ia/IIa 807 C/T (873 G/A), and P2Y1 polymorphisms are mentioned as causes of aspirin resistance. Coadministration of ibuprofen is mentioned as a cause of aspirin resistance, but it can probably explain only a small part of the aspirinresistant cases, which makes it more likely that aspirin resistance is an important cause of cardiovascular events in patients taking aspirin and ibuprofen, instead of an interaction with ibuprofen. The Food and Drug Administration (FDA) recently issued a warning on the concomitant use of aspirin and ibuprofen and added a timing advice (for taking aspirin at least 30min before and no more than 8 h after taking ibuprofen), which was based on the above-mentioned ex vivo data. In our opinion, more data need to be collected before such a warning is presented to the public. In patients experiencing thrombotic events despite aspirin and concomitant ibuprofen use, aspirin resistance and genetic polymorphisms need to be investigated.

Multislice Spiral Computed Tomography–Assisted Vein Graft Stenting

A 73-year-old woman presented with angina pectoris 2 years after bypass surgery with left internal mammary artery to left anterior descending coronary artery and a saphenous vein graft (SVG) to the obtuse marginal branch (OM) and the posterior descending artery (PDA).nnOn admission, the chest radiograph showed an enlarged mediastinum; no pleural effusion was present. An ECG-gated multislice spiral computed tomography (MSCT) was performed. Axial (Figure 1A) and 3D volume–rendered (Figure 1B) images showed a subacute …