Valeria Ferrero

Long-term histological and immunohistochemical findings in human venous aorto-coronary bypass grafts

The aim of the present study was to analyse the long-term histology and immunohistochemistry of the plaque composition and cellular infiltration of SVGs (saphenous vein grafts) containing metallic stents. Percutaneous interventions in SVGs have a worse long-term clinical outcome compared with stenting of coronary arteries. Whether the pathological features of old degenerated SVGs condition the efficacy of drug-eluting stents is also unknown. Histology and immunohistochemistry of seven SVGs in the coronary circulation containing 12 metallic stents implanted 5 to 61 months before retrieval were analysed in patients undergoing a second aorto-coronary bypass surgery at a mean time of 11+/-6 years. The pathology of the old SVGs showed an important thrombotic and necrotic composition of the plaque, with plaque protrusion through the stent wires and a fragile media layer that could easily be damaged by stent placement with subsequent neointimal proliferation; indeed, stents with medial fracture had significantly greater mean neointimal thickness than those without (1.37+/-0.68 compared with 0.81+/-0.47 mm(2); P<0.02). Neointimal inflammatory cell density correlated with increased neointimal thickness in patent vessels (r(2)=0.43, P<0.001). Immunostaining showed the total absence of ERs (oestrogen receptors), a poor cellular proliferative state as indicated by the presence of the Ki-67 marker, and persistent inflammation close to the stent wires as revealed by KP-1 and ACE (angiotensin-converting enzyme) immunostaining in most inflammatory cells in contact with the metal. These pathological findings may contribute to the more severe progression of disease and worse clinical outcome observed after conventional stented angioplasty of SVGs and might also interfere with the efficacy of drug-eluting stents in this specific atherosclerotic milieu.

Immunosuppressive therapy with oral prednisone to prevent restenosis after PCI. A multicenter randomized trial

BACKGROUNDnPrednisone at immunosuppressive doses after stenting has shown remarkable efficacy in reducing ischemic recurrences in nondiabetic patients with high post-procedural levels of C-reactive protein; the study aim was to compare the clinical outcome obtained in a control group of patients treated with bare metal stents versus 2 other study groups--bare metal stent plus oral prednisone or drug eluting stents--assuming similar optimal adjunctive medical treatment.nnnMETHODSnFive tertiary Italian hospitals enrolled 375 nondiabetic patients with coronary artery disease and no contraindications to dual antiplatelet treatment or corticosteroid therapy in a randomized, controlled study performed between 2007 and 2009. Patients were allocated into 3 study groups: bare metal stents (controls), bare metal stents followed by a 40-day prednisone treatment, or drug-eluting stents. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischemia needing repeated target vessel revascularization at 1 year as adjudicated by an independent clinical events committee.nnnRESULTSnOne-year follow-up was obtained in all patients. Patients receiving bare metal stents alone as compared to those treated with prednisone or drug-eluting stents had lower event-free survival; the primary endpoint was 80.8% in controls compared to 88.0% in the prednisone and 88.8% in the drug-eluting stent groups, respectively (P=.04 and .006).nnnCONCLUSIONnCompared with bare metal stents alone, prednisone treatment after bare metal stents or drug-eluting stent implantation result in a better event-free survival at 1 year.

Glucocorticoids in the prevention of restenosis after coronary angioplasty: therapeutic potential.

Vessel luminal narrowing after percutaneous coronary intervention (PCI) is characterised by platelet aggregation, release of growth factors, inflammatory cell infiltration, medial smooth muscle cell (SMC) proliferation, proteoglycan deposition and extracellular matrix remodelling. It is broadly accepted that the central mechanism at the basis of the whole pathophysiological process of restenosis is inflammation, triggered by vascular injury and activated through autocrine or paracrine mediators. Glucocorticosteroids exert beneficial effects on platelet function, on SMC proliferation and on collagen synthesis as well as inflammatory cell migration and activation, thus interfering with several steps of the cascade leading to neointima formation and subsequent late lumen loss.Initial experiences with systemic administration of glucocorticoids after PCI failed to confirm the expected benefits of this treatment, probably as a result of inadequate dosage and pharmacokinetic calculations. Recently a short-term, high-dose immunosuppressive treatment scheme with oral prednisone has demonstrated remarkable clinical and angiographic results when prednisone was given orally at a dose of 1 mg/kg for 10 days, 0.5 mg/kg for 20 days and 0.25 mg/kg for 15 days. This treatment has dramatically reduced the incidence of clinical vascular events at 1 year compared with controls (relative risk 0.34; 95% CI 0.12, 0.96; p = 0.006) and reduced the incidence of angiographic restenosis below 10% in different clinical and angiographie subsets. Secondary effects of a short course of glucocorticoids are generally minor, predictable and reversible: gastric pain, water and salt retention and worsened hypertension manifest in nearly 10% of patients. The addition of diuretics and acid suppressants before discharge, and the upgrading of antihypertensive medication thereafter, if needed, are useful preventive measures to control these temporary disorders. A routine blood cell count 4 weeks after PCI is advised in patients receiving thienopyridines (clopidogrel or ticlopidine) in addition to prednisone to rule out infrequent haematological dyscrasias.Emerging evidence supports this strategy as a convenient and well tolerated alternative to more expensive and complex revascularisation procedures such as drug eluting stent (DES) implantation or cardiac surgery, provided that the treatment is reserved for carefully selected candidates, i.e. after the exclusion of those with diabetes mellitus, a recent transmural myocardial infarction, or contraindications to the administration of a short-course of high-dose glucocorticoster-oids. The recent concerns regarding the long-term safety of first-generation DES and the as yet undetermined duration of dual anti-platelet treatment, further supports the need for a simple pharmacological treatment that can be applied in a large percentage of patients currently treated with PCI. Multicentre randomised studies aimed at defining the efficacy and safety of oral prednisone treatment compared with metallic stents and DES are ongoing, and will become available in upcoming years.

Functional Assessment of Coronary Artery Disease in Patients Undergoing Transcatheter Aortic Valve Implantation: Influence of Pressure Overload on the Evaluation of Lesions Severity

Background—Aortic valve stenosis may influence fractional flow reserve (FFR) of concomitant coronary artery disease by causing hypertrophy and reducing the vasodilatory reserve of the coronary circulation. We sought to investigate whether FFR values might change after valve replacement. Methods and Results—The functional relevance of 133 coronary lesions was assessed by FFR in 54 patients with severe aortic valve stenosis before and after transcatheter aortic valve implantation (TAVI) during the same procedure. A linear mixed model was used to verify the interaction of TAVI effect with the FFR values. No significant overall change in FFR values was found before and after the aortic valve stenosis removal (0.89±0.10 versus 0.89±0.13; P=0.73). A different trend in FFR groups (positive if ⩽0.8; negative if >0.8) was found after TAVI (P for interaction <0.001). Positive FFR values worsened after TAVI (0.71±0.11 versus 0.66±0.14). Conversely, negative FFR values improved after TAVI (0.92±0.06 versus 0.93±0.07). Similarly, FFR values in coronary arteries with lesions presenting percent diameter stenosis >50 worsened after TAVI (0.84±0.12 versus 0.82±0.16; P=0.02), whereas FFR values in arteries with mild lesions (percent diameter stenosis <50) tended toward improvement after TAVI (0.90±0.07 versus 0.91±0.09; P=0.69). Functional FFR variations after TAVI changed the indication to treat the coronary stenosis in 8 of 133 (6%) lesions. Conclusions—Coronary hemodynamics are influenced by aortic valve stenosis removal. Nevertheless, FFR variations after TAVI are minor and crossed the diagnostic cutoff of 0.8 in a small number of patients after valve replacement. Borderline coronary lesions might become functionally significant after valve replacement, although FFR-guided interventions were infrequent even in patients with angiographically significant lesions.

Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES)

AIMSnTo analyse the clinical outcome at 4 years in patients with coronary artery disease treated with bare metal stents (BMS) vs. BMS and oral prednisone, or drug-eluting stents (DES), all assuming similar adjunctive medical treatment.nnnMETHODS AND RESULTSnFive Italian hospitals enrolled 375 non-diabetic, ischaemic patients without contraindications to dual anti-platelet treatment or corticosteroid therapy in a randomized controlled study. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischaemia needing repeated target vessel revascularization at 1 year, and this was significantly lower in the BMS group (80.8%) compared with the prednisone (88.0%) and DES group (88.8%, P = 0.04 and 0.006, respectively). The long-term analysis of the primary endpoint was a pre-specified aim of the trial, and was performed at 1447 days (median, IQ range = 1210-1641). Patients receiving BMS alone had significantly lower event-free survival (75.3%) compared with 84.1% in the prednisone group (HR: 0.447; 95% CI: 0.25-0.80, P = 0.007) and 80.6% in DES patients (HR: 0.519; 95% CI: 0.29-0.93, P = 0.03). Prednisone-treated patients did not develop new treatment-related clinical problems. Drug-eluting stents patients suffered more very late stent thrombosis as a cause of spontaneous myocardial infarction. The need for target vessel revascularization remained lower in the prednisone and DES groups (13.6 and 15.2%, respectively), compared with BMS (23.2%).nnnCONCLUSIONSnThe clinical benefits of prednisone compared with BMS only persisted almost unchanged at 4 years. Drug-eluting stents performed better than BMS at long-term, although the advantages observed at 1 year were in part attenuated because of the occurrence of very late stent thrombosis and late revascularizations. Clinical Trial NCT 00369356.

Tobacco smoke affects expression of peroxisome proliferator-activated receptor-γ in monocyte/macrophages of patients with coronary heart disease

Background and purpose:u2002 Tobacco smoke represents a relevant risk factor for coronary heart disease (CHD). Although peroxisome proliferator‐activated receptor (PPAR)γ activation reduces inflammation and atherosclerosis, expression of PPARγ in cells and its modulation by smoking are poorly investigated. We previously reported that monocyte/macrophages from healthy smokers exhibited an enhanced constitutive expression of PPARγ. Here, we evaluated PPARγ expression and basal cytokine release in monocytes and monocyte‐derived macrophages (MDMs) from 85 CHD patients, classified by their smoking habit (smokers, non‐smokers and ex‐smokers), and assessed the role of PPARγ ligands in this context.

Cytokines release inhibition from activated monocytes, and reduction of in-stent neointimal growth in humans.

OBJECTIVEnAtherosclerosis and restenosis are largely ruled by inflammation. The aim of this study was to test the effects of a short-course, high-dose oral prednisone on the release of interleukin-6 (IL-6) and tumour necrosis factor (TNF)-alpha from circulating monocytes and on the neointimal growth that follows bare metal stent (BMS) implantation. In a sub-group of patients activated NF-kappaB was also evaluated.nnnMETHODSnOut of 40 patients with coronary artery disease treated with BMS implantation, 20 were randomly assigned to receive oral prednisone during 40 days according to a standardized protocol. In non-stimulated and stimulated (LPS and PMA) monocytes we evaluated the release of IL-6 and TNF-alpha, and NF-kappaB p50 subunit translocation at baseline, at 10 and 30 days. Late luminal loss (LLL) 9 months after angioplasty was calculated by quantitative coronary angiography.nnnRESULTSnPlasma concentrations of prednisone correlated inversely with IL-6 and TNF-alpha release (R2=0.45, p=0.04 and R2=0.69, p=0.005, respectively) and NF-kappaB activation from monocytes (R2=0.58, p=0.01). The reduction of TNF-alpha release and NF-kappaB activation were significantly related (R2=0.56, p=0.01). Prednisone patients showed a significantly larger reduction of cytokine release and NF-kappaB activation compared to non-treated patients, at 10 days and 30 days. LLL was lower in the prednisone group (0.44+/-0.35 mm versus 0.80+/-0.53 mm, p=0.02) and correlated with reduction of TNF-alpha (R2=0.41, p=0.01).nnnCONCLUSIONSnHigh doses of oral prednisone reduce NF-kappaB pathway activation and pro-inflammatory cytokine release in circulating activated monocytes of patients treated with coronary stenting. TNF-alpha release reduction correlates with decreased LLL.

Coronary Vasomotion One Year after Drug-Eluting Stent Implantation: Comparison of Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents

First-generation drug-eluting stents (DES) have been associated with impaired localized coronary vasomotion and delayed endothelialization. We aimed to compare coronary vasomotion after implantation of a newer-generation everolimus-eluting stent (EES), with a first-generation paclitaxel-eluting stent (PES). Coronary vasomotion was studied in 19 patients with EES and 13 with PES. Vasomotor response was measured proximally and distally to the stent and in a remote vessel (reference segment). Quantitative coronary angiography was performed offline. Endothelium independent vasomotion did not differ significantly between the two groups. EES showed significant vasodilatation while PES showed vasoconstriction at both proximal (+4.5u2009±u20093.6 vs −4.2u2009±u20096.9, pu2009<u20090.001) and distal (+4.6u2009±u20097.9 vs −4.8u2009±u20099.3, pu2009=u20090.003) segments. The reference segment did not show any significant difference in vasodilatation between the two groups (+9.8u2009±u20096.4 vs +7.2u2009±u20095.2, pu2009=u20090.17). Endothelium-dependent vasomotion at adjacent stent segments is relatively preserved after EES implantation while vasoconstriction was observed after PES implantation.

Coronary Catheterization and Percutaneous Interventions After Transcatheter Aortic Valve Implantation

Coronary artery disease (CAD) is often present in patients with severe aortic valve stenosis candidates to transcatheter aortic valve implantation (TAVI). Mild CAD may also worsen and need treatment years after TAVI. The implantation of a transcatheter valve may interfere with the capability of reengaging the coronary arteries. We prospectively assessed the feasibility of performing coronary angiography (CA), fractional flow reserve, and, where indicated, percutaneous coronary intervention after valve implantation in a consecutive series of patients with CAD undergoing TAVI. Valve type and size were decided according to accurate computed tomography scan and angiographic measurement of the aortic root structures. We analyzed 66 consecutive patients undergoing TAVI, 41 with balloon-expandable, and 25 with self-expandable transcatheter valves. Right and left coronary catheterization (132 vessels) was successful in all cases except in 1 left coronary artery after a high implantation of a self-expandable valve (unsuccess rate, 1 in 50 vessels). In 6 of 132 vessels (4%), CA was initially nonselective, but after positioning the 0.014″ intracoronary guidewire, selective injections were obtained in all these cases. Percutaneous coronary intervention was performed successfully in 19 coronary vessels (17 patients) as indicated by fractional flow reserve measurements. In conclusion, catheterization of the coronary ostia after transfemoral TAVI with balloon or self-expandable valves is safe and feasible in almost all cases. Accurate imaging of the aortic root and procedural planning may help to avoid too high implantation of supra-annular self-expandable valves to obviate difficulties in accessing coronary ostia. Use of intracoronary guidewires facilitates selective CA in cases with difficult access.

Late and very late coronary stent thrombosis: Intravascular ultrasound findings and associations with antiplatelet therapy

Late and very‐late stent occlusion remains a serious complication of coronary stenting. Despite their high anti‐restenotic efficacy, drug‐eluting stents (DES) have been associated to more late‐thrombosis as compared to bare‐metal stents (BMS). The aim of this study is to analyze the clinical presentation, angiographic, and intravascular ultrasound (IVUS) findings in patients with late or very late stent thrombosis and the relationship with the antiplatelet regimen.