Impact of drug-eluting balloon (pre- or post-) dilation on neointima formation in de novo lesions treated by bare-metal stent: the IN-PACT CORO trial

The efficacy of DEB in modifying the high restenosis risk associated with BMS implantation is doubtful. Optical coherence tomography (OCT) may allow precise assessment of neointimal formation after stent implantation. We performed a single-center, prospective, 1:2 randomized trial comparing BMS implantation alone (BMS group) vs. additional DEB (DEB group). DEB patients were further randomized 1:1 to DEB before stenting (pre-DEB group), or after stenting (post-DEB group). Primary endpoint was OCT-assessed neointimal hyperplasia (expressed both as mean in-stent neointimal area and as percentage obstruction of the mean stent area) at 6 months. Secondary endpoints were the percentage of uncovered and malapposed stent struts. Thirty patients were enrolled and randomized to BMS (n = 10), pre-DEB (n = 10), post-DEB (n = 10). At 6-month OCT follow-up, DEB significantly reduced neointimal area compared with BMS: mean neointimal area 2.01 ± 0.89 vs. 3.03 ± 1.07 mm² (p = 0.02), percentage area obstruction 24.56 ± 12.50 vs. 37.51 ± 12.26 % (p = 0.02). The percentage of uncovered and malapposed stent struts did not differ significantly between BMS and DEB. In the comparison between pre-DEB and post-DEB, no significant difference was observed for both primary and secondary endpoints. In de novo coronary lesions treated with BMS, DEB use could be associated with a mild reduction in neointimal hyperplasia at 6 months; this effect could be unrelated to the timing of DEB dilation (pre- or post-stenting).Clinical Trial Registration Information: http://www.clinicaltrials.gov. Identifier: NCT01057563.     

Endothelin-1 and acute myocardial infarction: a no-reflow mediator after successful percutaneous myocardial revascularization.

AIMS: No-reflow after a primary percutaneous coronary intervention (PCI) is associated with a high incidence of left ventricular (LV) failure and a poor prognosis. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide and an important modulator of neutrophil function. Elevated systemic ET-1 levels have recently been reported to predict a poor prognosis in patients with acute myocardial infarction (AMI) treated by primary PCI. We aimed to investigate the relationship between systemic ET-1 plasma levels and no-reflow in a group of AMI patients treated by primary PCI. METHODS AND RESULTS: A group of 51 patients (age 59+/-9.9 years, 44 males) with a first AMI, undergoing successful primary or rescue PCI, were included in the study. Angiographic no-reflow was defined as coronary TIMI flow grade < or =2 or TIMI flow 3 with a final myocardial blush grade < or =2. Blood samples were obtained from all patients on admission for ET-1 levels measurement. No reflow was observed in 31 patients (61%). Variables associated with no-reflow at univariate analysis included culprit lesion of the left anterior coronary descending artery (LAD) (67 vs. 29%, P=0.006) and ET-1 plasma levels (3.95+/-0.7 vs. 3.3+/-0.8 pg/mL, P=0.004). At multivariable logistic regression analysis, ET-1 was the only significant predictor of no-reflow (P=0.03) together with LAD as the culprit vessel (P=0.04). CONCLUSION: ET-1 plasma levels predict angiographic no-reflow after successful primary or rescue PCI. These findings suggest that ET-1 antagonists might be beneficial in the management of no-reflow.     

Different ploidy levels of megakaryocytes generated from peripheral or cord blood CD34+ cells are correlated with different levels of platelet release

Ploidy could be the key to understanding megakaryocyte (MK) biologyand platelet production. Human CD34⁺ cells purified fromumbilical cord blood (CB) and peripheral blood (PB) were investigatedon their capability to give rise, in a serum-free medium containingthrombopoietin, to MKs and platelets. CB-MKs showed reducedpolyploidization and platelet number compared with PB-MKs, but asimilar membrane phenotype. Most CB-MKs showed a 2N content of DNA(~80%) and only 2.6% had 8N, whereas 40% of the PB cells had 8N ormore. Platelets were substantially released in PB culture from day 12;at day 14 the CB-derived MKs were able to release platelets although ata reduced level (~35%), correlating with their reduced size. Adirect correlation was demonstrated by sorting polyploid cells fromPB-MKs and evaluating the platelets released in the supernatant.Furthermore, the study analyzed the expression and distribution ofcyclin D3 and cyclin B1. Cyclin D3 protein was increased in PB incomparison to CB-MKs; in PB culture most cells rapidly became positive,whereas in CB-derived cells cyclin D3 expression was evident only fromday 9 and in a reduced percentage. Cyclin B1 was essentially localizedat the nuclear level in the CB and was expressed during the wholeculture. In PB-MKs, at day 9, a reduction was observed, correlatingwith an advanced ploidy state. The data indicate the inability of the CB-MKs to progress in the endomitotic process and a direct correlation between DNA content and platelet production.     

Three-year Follow-up of Patients With Bifurcation Lesions Treated With Sirolimus- or Everolimus-eluting Stents: SEAside and CORpal Cooperative Study

Introduction and objectives

To compare the 3-year incidence of major events in patients with bifurcation lesions treated with provisional sirolimus-eluting stents vs everolimus-eluting stents.

Methods

A pooled analysis of 2 prospective randomized trials with similar methodology (SEAside and CORpal) was performed. In these trials, 443 patients with bifurcation lesions were randomly assigned to treatment with either sirolimus-eluting stents or everolimus-eluting stents. The clinical follow-up was extended up to 3 years to assess major adverse cardiovascular events (death or acute myocardial infarction or target vessel revascularization).

Results

At 3 years, survival free of major adverse cardiovascular events was 93.2% vs 91.3% in the everolimus-eluting stent group vs the sirolimus-eluting stent group (P = .16). Exploratory land-mark analysis for late events (occurring after 12 months) showed significantly fewer major adverse cardiovascular events in the everolimus-eluting stent group: 1.4% vs 5.4% in the sirolimus-eluting stent group (P = .02).

Conclusions

Provisional stenting with either sirolimus-eluting stents or everolimus-eluting stents in bifurcation lesions is associated with low rates of major adverse events at 3-years’ follow-up. The results of a subanalysis of events beyond 1 year, showing a lower event rate with everolimus-eluting stents than with sirolimus-eluting stents, suggest that studies exploring the long-term clinical benefit of the latest generation of drug-eluting stents are warranted.     

Advances in mechanisms,imaging and management of the unstable plaque

Post-mortem observations demonstrated that plaque fissure was the final event leading to coronary thrombosis and occlusion in about two-thirds of cases of sudden coronary death. Plaques prone to fissure have, therefore, been defined “vulnerable plaques” and are identified by specific anatomic features including thin inflamed fibrous cap, large lipidic core and positive remodeling. Accordingly, elegant imaging modalities have been developed in order to identify this “holy grail”. However, the results of prognostic studies based on the identification of vulnerable plaques have not been encouraging because of the low positive predictive value for major cardiovascular events. This observation is not surprising as the pathogenesis of acute coronary syndromes is complex and multifactorial. In this review we propose a pathogenetic classification of acute coronary syndromes in the attempt to identify homogeneous groups of patients with a common mechanism of coronary instability which can be identified by using specific biomarkers and imaging techniques, and become a specific therapeutic target.     

Relative risk of plaque erosion among different age and sex groups in patients with acute coronary syndrome

Postmortem studies reported plaque erosion is frequent in young women. Recent in vivo studies failed to show age and sex differences in the plaque erosion prevalence. The aim of this study was to investigate the prevalence of plaque erosion by age and sex among acute coronary syndromes (ACS) patients. From 1699 ACS patients, 1083 with plaque erosion or rupture were analyzed. Patients were categorized as 5 age groups (≤?50, 51–60, 61–70, 71–80,?≥?81 years). Overall prevalence of plaque erosion was similar between males and females (p?=?0.831). Males age?≤?50 had higher (p?=?0.018) and age 71–80 had lower (p?=?0.006) prevalence of plaque erosion. Females age 61–70 had higher (p?=?0.021) and age 71–80 had lower (p?=?0.045) prevalence of plaque erosion. In advanced age groups (≥?71 years), rupture was the dominant etiology in both sexes. In multivariate analysis of males, age?≤?50 demonstrated a trend to increase (OR 1.418, 95% CI 0.961–2.093, p?=?0.078) the erosion risk. Females age?≤?70 independently increased (OR 2.138, 95% CI 1.249–3.661, p?=?0.006) the risk for erosion. The prevalence of plaque erosion was similar between males and females. Plaque erosion risk was increased in the males age?≤?50 and in the females age?≤?70 among ACS patients.

     

Differential immunohistochemical detection of transforming growth factor α, amphiregulin and CRIPTO in human normal and malignant breast tissues

The expression of growth factors, such as transforming growth factor α (TGFα), amphiregulin (AR) and CRIPTO, a type-1 tyrosine-kinase growth factor receptor-(erbB-2), and a tumor-suppressor gene (p53), that have been implicated in the development and/or the progression of breast cancer, was evaluated by immunohistochemistry in 100 human primary infiltrating breast carcinomas (IBC). AR and CRIPTO immunoreactivity was also assessed in 55 human breast ductal carcinomas in situ (DCIS). Within the 100 IBC, 80, 50, 73, 17, and 34 tumors expressed moderate to high levels of TGFα, AR, CRIPTO, erbB-2, and p53 respectively. In addition, AR and CRIPTO immunoreactivity were found in 11 and in 26 out of 55 DCIS respectively. In contrast, only 4, 3, and 2 out of 10 normal mammary-gland samples were weakly positive for TGFα, AR, and CRIPTO expression, respectively, whereas none was positive for erbB-2 or p53. Within the 100 IBC, expression of erbB-2 significantly correlated with high histologic and nuclear grading, with high growth fraction, and with estrogen-receptor(ER)- and progesterone-receptor(PgR)-negative tumors. A statistically significant correlation was also observed between p53 expression and high histologic grading, high growth fraction, and PgR-negative tumors. In contrast, no significant correlations were found between TGFα, AR, and CRIPTO immunoreactivity and various clinicopathological parameters, with the exception of a positive correlation between TGFα and ER expression. These data demonstrate that TGFα, AR, and CRIPTO expression are significantly increased in malignant mammary epithelium relative to normal epithelium. In particular, the differential expression of CRIPTO may serve as a potential tumor marker for breast carcinogenesis. © 1996 Wiley-Liss, Inc.     

Effects of Tafamidis on Transthyretin Stabilization and Clinical Outcomes in Patients with Non-Val30Met Transthyretin Amyloidosis

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7 %) of 19 patients with evaluable data. TTR was stabilized in 100 % of patients with non-missing data at Months 6 (n?=?18) and 12 (n?=?17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.     

Myocardial Contrast Echocardiography Versus Dobutamine Echocardiography for Predicting Functional Recovery After Acute Myocardial Infarction Treated With Primary Coronary Angioplasty

Objectives. We sought to compare myocardial contrast echocardiography with low dose dobutamine echocardiography for predicting 1-month recovery of ventricular function in acute myocardial infarction treated with primary coronary angioplasty.

Background. The relation between myocardial perfusion and contractile reserve in patients with acute myocardial infarction, in whom anterograde flow is fully restored without significant residual stenosis, is still unclear.

Methods. Thirty patients with acute myocardial infarction treated successfully with primary coronary angioplasty underwent intracoronary contrast echocardiography before and after angioplasty and dobutamine echocardiography 3 days after the index infarction. One month later, two-dimensional echocardiography and coronary angiography were repeated in all patients and contrast echocardiography in 18 patients.

Results. After coronary recanalization, 26 patients showed myocardial reperfusion within the risk area, although 4 did not. At 1-month follow-up, all patients had a patent infarct-related artery without significant restenosis. Both left ventricular ejection fraction and wall motion score index within the risk area significantly improved in the patients with reperfusion ([mean ± SD] 38 ± 8% vs. 48 ± 12%, p < 0.005; and 2.35 ± 0.5 vs. 2 ± 0.6, p < 0.001, respectively), but not in those with no reflow. Of the 72 nonperfused segments before angioplasty, 27 showed functional improvement at follow-up. Myocardial contrast echocardiography had a sensitivity and a negative predictive value similar to dobutamine echocardiography in predicting late functional recovery (96% vs. 89% and 89% vs. 93%, respectively), but a lower specificity (18% vs. 91%, p < 0.001), positive predictive value (41% vs. 86%, p < 0.001) and overall accuracy (47% vs. 90%, p < 0.001).

Conclusions. Microvascular integrity is a prerequisite for myocardial viability after acute myocardial infarction. However, contrast enhancement shortly after recanalization does not necessarily imply a late functional improvement. Thus, contractile reserve elicited by low dose dobutamine is a more accurate predictor of regional functional recovery after reperfused acute myocardial infarction than microvascular integrity.

(J Am Coll Cardiol 1996;28:1677–83)>