Comparison of prasugrel and clopidogrel-treated patients with acute coronary syndrome undergoing percutaneous coronary intervention: A propensity score-matched analysis of the Acute Myocardial Infarction in Switzerland (AMIS)-Plus Registry.

OBJECTIVE: The purpose of this study was to investigate outcomes of patients treated with prasugrel or clopidogrel after percutaneous coronary intervention (PCI) in a nationwide acute coronary syndrome (ACS) registry. BACKGROUND: Prasugrel was found to be superior to clopidogrel in a randomized trial of ACS patients undergoing PCI. However, little is known about its efficacy in everyday practice. METHODS: All ACS patients enrolled in the Acute Myocardial Infarction in Switzerland (AMIS)-Plus registry undergoing PCI and being treated with a thienopyridine P2Y12 inhibitor between January 2010-December 2013 were included in this analysis. Patients were stratified according to treatment with prasugrel or clopidogrel and outcomes were compared using propensity score matching. The primary endpoint was a composite of death, recurrent infarction and stroke at hospital discharge. RESULTS: Out of 7621 patients, 2891 received prasugrel (38%) and 4730 received clopidogrel (62%). Independent predictors of in-hospital mortality were age, Killip class >2, STEMI, Charlson comorbidity index >1, and resuscitation prior to admission. After propensity score matching (2301 patients per group), the primary endpoint was significantly lower in prasugrel-treated patients (3.0% vs 4.3%; p=0.022) while bleeding events were more frequent (4.1% vs 3.0%; p=0.048). In-hospital mortality was significantly reduced (1.8% vs 3.1%; p=0.004), but no significant differences were observed in rates of recurrent infarction (0.8% vs 0.7%; p=1.00) or stroke (0.5% vs 0.6%; p=0.85). In a predefined subset of matched patients with one-year follow-up (n=1226), mortality between discharge and one year was not significantly reduced in prasugrel-treated patients (1.3% vs 1.9%, p=0.38). CONCLUSIONS: In everyday practice in Switzerland, prasugrel is predominantly used in younger patients with STEMI undergoing primary PCI. A propensity score-matched analysis suggests a mortality benefit from prasugrel compared with clopidogrel in these patients.

[Follow-up care of patients after heart attack]. / Nachsorge von Herzinfarktpatienten in der Hausarztpraxis.

Survivors of a myocardial infarction are at increased risk for future cardiac events, including recurrent infarction, heart failure, arrhythmia, stroke, and sudden cardiac death. The primary care physician needs to be aware of the potential risks and complications facing these patients. Secondary preventive measures after myocardial infarction include an optimal medical therapy (dual antiplatelet therapy, Statin, ACE-inhibitor, and in most cases a beta-blocker) and life style modifications (quit smoking, regular physical activity, Mediterranean-style diet). Patients should be informed about how to recognize and react to cardiac symptoms.

Long-term efficacy and safety of biodegradable-polymer biolimus-eluting stents: main results of the Basel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination II (BASKET-PROVE II), a randomized, controlled noninferiority 2-year outcome trial.

BACKGROUND: Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. METHODS AND RESULTS: To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9-eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide-coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; -1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, -5.16; -8.32 to -2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. CONCLUSIONS: In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.

Epigenetic regulation of tissue factor inducibility in endothelial cell senescence.

Cellular senescence, a programmed state induced by multiple deleterious triggers, is characterised by permanent cell-cycle exit and altered gene expression and cell morphology. In humans it is considered a tumor suppressor mechanism, mediating removal of damaged or mutated cells from the cell-cycle pool, and may also contribute to the ageing process. In this study, we show that senescent human umbilical vein endothelial cells lose their ability to induce tissue factor (TF), a transmembrane protein with important roles in hemostasis and cancer progression, in response to thrombin or - independently of cell-surface receptors - phorbol-12-myristate-13-acetate. This phenomenon could not be explained by senescence-related alterations in the downstream signal transduction cascade or by accelerated TF mRNA degradation. Rather, using chromatin immuno-precipitation we could show that loss of TF gene inducibility during senescence occurs following chromatin remodelling of the TF promoter resulting from hypo-acetylation of histone H3. These findings were reversible after transduction of presenescent cultures with telomerase reverse transcriptase, enabling late-passage cultures to escape senescence. These results extend the involvement of heterochromatic gene silencing in senescence beyond cell cycle-related genes and suggest a novel anti-cancer mechanism of senescence through inhibition of TF inducibility.

Long-term survival and functional outcome of unselected patients undergoing percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: Percutaneous coronary intervention (PCI) is the most effective reperfusion modality in patients with acute myocardial infarction (MI). Data concerning long-term survival and functional outcome are sparse. METHODS: One thousand consecutive patients treated by emergency PCI were systematically ana-lysed in a single-centre registry. Multivariate predictors of in-hospital mortality, post-discharge mortality and late functional capacity were identified. RESULTS: Follow-up was completed for 978 patients. The median clinical follow-up length was 3.2 years. In-hospital and post-discharge mortality were 7.6% and 7.3%, respectively. Annualised post-discharge mortality remained stable over time at 2% per year. Independent predictors of in-hospital death were cardiogenic shock, TIMI flow <3 after PCI, left ventricular ejection fraction <40%, age and time to patent artery >6 h. Independent predictors of post-discharge mortality were TIMI flow after PCI <3, prior MI, elevated glucose levels at admission, and increasing age. In contrast, cardiogenic shock, time to patent artery and left ventricular ejection fraction <40% were not independently associated with post-hospital death. At late follow-up, 47% of patients had normal functional capacity and 49.1% were in New York Heart Association functional class II. Predictors of impaired functional capacity at follow-up were age, gender, smoking habits and multivessel coronary disease. CONCLUSIONS: Post-discharge mortality after PCI for acute MI was 2% per year. Significant differences exist between predictors of in-hospital and post-discharge mortality. The functional capacity of surviving patients was remarkably good, even when presented in cardiogenic shock.

Differential regulation of telomerase in endothelial cells by fibroblast growth factor-2 and vascular endothelial growth factor-a: association with replicative life span.

In cultured human umbilical vein endothelial cells (HUVECs), fibroblast growth factor-2 (FGF-2), but not vascular endothelial growth factor-A (VEGF-A), upregulates telomerase activity. Here, we examined the functional significance of this differential regulation on the replicative life span of HUVECs. HUVECs were serially passaged until senescence under four different conditions: (1) EGM-2, a medium containing both VEGF-A and FGF-2; (2) basal medium (BM), consisting of EGM-2 devoid of FGF-2 and VEGF-A; (3) BM supplemented with FGF-2; and (4) BM supplemented with VEGF-A. Cells cultured in BM demonstrated decreased growth rate and ceased to proliferate at approximately 15 population doublings (PDs), whereas those cultured with VEGF-A alone initially proliferated vigorously but arrested growth abruptly at a PD level comparable with cultures grown in BM. In contrast, cells maintained in EGM-2 or in BM/FGF-2 attained a normal replicative life span (approximately 40 PDs). These differences in replicative behavior were reflected by the early appearance of a senescent phenotype in cultures grown in BM or BM/VEGF-A. HUVECs grown in the presence of VEGF-A alone have a decreased life span compared with cultures maintained with FGF-2. This suggests that the upregulation of telomerase activity by FGF-2, an effect not achieved with VEGF-A, plays a functional role in preventing the early onset of senescence.

Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells.

Replicative senescence and oxidative stress have been implicated in ageing, endothelial dysfunction and atherosclerosis. Replicative senescence is determined primarily by telomere integrity. In endothelial cells the glutathione redox-cycle plays a predominant role in the detoxification of peroxides. The aim of this study was to elucidate the role of the glutathione-dependent antioxidant system on the replicative capacity and telomere dynamics of cultured endothelial cells. Human umbilical vein endothelial cells were serially passaged while exposed to regular treatment with 0.1 microM tert-butyl hydroperoxide, a substrate of glutathione peroxidase, or 10 microM L-buthionine-[S,R]-sulphoximine, an inhibitor of glutathione synthesis. Both treatments induced intracellular oxidative stress but had no cytotoxic or cytostatic effects. Nonetheless, treated cultures entered senescence prematurely (30 versus 46 population doublings), as determined by senescence-associated beta-galactosidase staining and a sharp decrease in cell density at confluence. In cultures subjected to oxidative stress terminal restriction fragment (TRF) analysis demonstrated faster telomere shortening (110 versus 55 bp/population doubling) and the appearance of distinct, long TRFs after more than 15-20 population doublings. Fluorescence in situ hybridisation analysis of metaphase spreads confirmed the presence of increased telomere length heterogeneity, and ruled out telomeric end-to-end fusions as the source of the long TRFs. The latter was also confirmed by Bal31 digestion of genomic DNA. Similarly, upregulation of telomerase could not account for the appearance of long TRFs, as oxidative stress induced a rapid and sustained decrease in this activity. These findings demonstrate a key role for glutathione-dependent redox homeostasis in the preservation of telomere function in endothelial cells and suggest that loss of telomere integrity is a major trigger for the onset of premature senescence under mild chronic oxidative stress.

Early atherogenesis in senescence-accelerated mice.

We studied atheromatous lesion formation in an animal model of accelerated ageing. The senescence-accelerated prone mouse (SAM-P) has a reduced life-span and exhibits clinical features characteristic of human ageing. Our aim was to establish whether these mice are more susceptible to atherosclerosis than a related strain, senescence-accelerated resistant mice (SAM-R), which age normally. We fed a Western-type diet to 14 SAM-P/8 and 14 SAM-R/1 mice for 17 weeks, starting at 28 weeks of age, measuring their serum lipid profiles before and after this diet. We stained aortic root cryostat cross-sections with Oil red O, and assessed lipid deposition morphometrically. We used immunohistochemistry to detect macrophages in the aortic roots. We found that despite showing similar alterations in lipid profile, SAM-P/8 mice developed more prevalent and extensive fatty lesions than SAM-R/1 mice. Furthermore, the lipid lesions in SAM-P/8 mice showed a greater frequency of invasion by macrophages. We conclude that mice, which age at an accelerated rate, are more prone to early atherogenesis than mice which age normally. We suggest that this increased susceptibility may result from abnormalities in the oxidative status and cellular replicative capacity of these mice.

Fibroblast growth factor-2, but not vascular endothelial growth factor, upregulates telomerase activity in human endothelial cells.

OBJECTIVE: Telomerase plays a major role in the control of replicative capacity, a critical property for successful angiogenesis and maintenance of endothelial integrity. In this study, we examined the relationship between telomerase activity and endothelial cell proliferation as well as the regulation of this enzyme by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF). METHODS AND RESULTS: Telomerase was repressed in endothelial cells freshly derived from intact endothelium, whereas activity was present during logarithmic growth in culture. In cultured human umbilical vein endothelial cells (HUVECs), mRNA levels of hTERT-the catalytic subunit of telomerase-and enzyme activity decreased reversibly on induction of quiescence. Treatment of quiescent HUVECs with FGF-2 restored telomerase activity in a time- and dose-dependent manner, whereas VEGF had no such effect, although both factors induced comparable mitogenic responses. FGF-2, but not VEGF, upregulated the mRNA levels for hTERT and for the hTERT gene transactivation factor Sp1. Serial passage in the presence of individual growth factors accelerated the accumulation of senescent cells in VEGF-treated cultures compared with cultures treated with FGF-2. CONCLUSIONS: FGF-2, but not VEGF, restores telomerase activity and maintains the replicative capacity of endothelial cells.