Metabolic labeling of RNA uncovers the contribution of transcription and decay rates on hypoxia-induced changes in RNA levels.

Cells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. However, most transcriptomic studies do not distinguish the relative contribution of transcription, RNA processing, and RNA degradation processes to cellular homeostasis. Here we used metabolic labeling followed by massive parallel sequencing of newly transcribed and preexisting RNA fractions to simultaneously analyze RNA synthesis and decay in primary endothelial cells exposed to low oxygen tension. We found that changes in transcription rates induced by hypoxia are the major determinant of changes in RNA levels. However, degradation rates also had a significant contribution, accounting for 24% of the observed variability in total mRNA. In addition, our results indicated that hypoxia led to a reduction of the overall mRNA stability from a median half-life in normoxia of 8.7 h, to 5.7 h in hypoxia. Analysis of RNA content per cell confirmed a decrease of both mRNA and total RNA in hypoxic samples and that this effect is dependent on the EGLN/HIF/TSC2 axis. This effect could potentially contribute to fundamental global responses such as inhibition of translation in hypoxia. In summary, our study provides a quantitative analysis of the contribution of RNA synthesis and stability to the transcriptional response to hypoxia and uncovers an unexpected effect on the latter.

Managing Perceived Loneliness and Social-Isolation Levels for Older Adults: A Survey with Focus on Wearables-Based Solutions.

As an inevitable process, the number of older adults is increasing in many countries worldwide. Two of the main problems that society is being confronted with more and more, in this respect, are the inter-related aspects of feelings of loneliness and social isolation among older adults. In particular, the ongoing COVID-19 crisis and its associated restrictions have exacerbated the loneliness and social-isolation problems. This paper is first and foremost a comprehensive survey of loneliness monitoring and management solutions, from the multidisciplinary perspective of technology, gerontology, socio-psychology, and urban built environment. In addition, our paper also investigates machine learning-based technological solutions with wearable-sensor data, suitable to measure, monitor, manage, and/or diminish the levels of loneliness and social isolation, when one also considers the constraints and characteristics coming from social science, gerontology, and architecture/urban built environments points of view. Compared to the existing state of the art, our work is unique from the cross-disciplinary point of view, because our authors' team combines the expertise from four distinct domains, i.e., gerontology, social psychology, architecture, and wireless technology in addressing the two inter-related problems of loneliness and social isolation in older adults. This work combines a cross-disciplinary survey of the literature in the four aforementioned domains with a proposed wearable-based technological solution, introduced first as a generic framework and, then, exemplified through a simple proof of concept with dummy data. As the main findings, we provide a comprehensive view on challenges and solutions in utilizing various technologies, particularly those carried by users, also known as wearables, to measure, manage, and/or diminish the social isolation and the perceived loneliness among older adults. In addition, we also summarize the identified solutions which can be used for measuring and monitoring various loneliness- and social isolation-related metrics, and we present and validate, through a simple proof-of-concept mechanism, an approach based on machine learning for predicting and estimating loneliness levels. Open research issues in this field are also discussed.

Older Adults' Loneliness, Social Isolation, and Physical Information and Communication Technology in the Era of Ambient Assisted Living: A Systematic Literature Review.

BACKGROUND: Loneliness and social isolation can have severe effects on human health and well-being. Partial solutions to combat these circumstances in demographically aging societies have been sought from the field of information and communication technology (ICT). OBJECTIVE: This systematic literature review investigates the research conducted on older adults' loneliness and social isolation, and physical ICTs, namely robots, wearables, and smart homes, in the era of ambient assisted living (AAL). The aim is to gain insight into how technology can help overcome loneliness and social isolation other than by fostering social communication with people and what the main open-ended challenges according to the reviewed studies are. METHODS: The data were collected from 7 bibliographic databases. A preliminary search resulted in 1271 entries that were screened based on predefined inclusion criteria. The characteristics of the selected studies were coded, and the results were summarized to answer our research questions. RESULTS: The final data set consisted of 23 empirical studies. We found out that ICT solutions such as smart homes can help detect and predict loneliness and social isolation, and technologies such as robotic pets and some other social robots can help alleviate loneliness to some extent. The main open-ended challenges across studies relate to the need for more robust study samples and study designs. Further, the reviewed studies report technology- and topic-specific open-ended challenges. CONCLUSIONS: Technology can help assess older adults' loneliness and social isolation, and alleviate loneliness without direct interaction with other people. The results are highly relevant in the COVID-19 era, where various social restrictions have been introduced all over the world, and the amount of research literature in this regard has increased recently.

Drosophila nuclear factor DREF regulates the expression of the mitochondrial DNA helicase and mitochondrial transcription factor B2 but not the mitochondrial translation factor B1.

DREF [DRE (DNA replication-related element)-binding factor] controls the transcription of numerous genes in Drosophila, many involved in nuclear DNA (nDNA) replication and cell proliferation, three in mitochondrial DNA (mtDNA) replication and two in mtDNA transcription termination. In this work, we have analysed the involvement of DREF in the expression of the known remaining genes engaged in the minimal mtDNA replication (d-mtDNA helicase) and transcription (the activator d-mtTFB2) machineries and of a gene involved in mitochondrial mRNA translation (d-mtTFB1). We have identified their transcriptional initiation sites and DRE sequences in their promoter regions. Gel-shift and chromatin immunoprecipitation assays demonstrate that DREF interacts in vitro and in vivo with the d-mtDNA helicase and d-mtTFB2, but not with the d-mtTFB1 promoters. Transient transfection assays in Drosophila S2 cells with mutated DRE motifs and truncated promoter regions show that DREF controls the transcription of d-mtDNA helicase and d-mtTFB2, but not that of d-mtTFB1. RNA interference of DREF in S2 cells reinforces these results showing a decrease in the mRNA levels of d-mtDNA helicase and d-mtTFB2 and no changes in those of the d-mtTFB1. These results link the genetic regulation of nuclear DNA replication with the genetic control of mtDNA replication and transcriptional activation in Drosophila.

Disturbed coronary hemodynamics in vessels with intermediate stenoses evaluated with fractional flow reserve: a combined analysis of epicardial and microcirculatory involvement in ischemic heart disease.

BACKGROUND: In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown. METHODS AND RESULTS: Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR>0.80 and CFR<2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75(th) percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR>0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR>0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4-31.8)] than those with FFR≤0.80 [17.3 (95% confidence interval, 13.0-21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR (r=-0.207, P=0.055), and in vessels with FFR>0.80 and CFR<2 (n=28, 39%), IMR had a wide dispersion (7-72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR≤0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation. CONCLUSIONS: A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.

Feasibility and safety of transfemoral implantation of Edwards SAPIEN XT prosthesis without balloon valvuloplasty in severe stenosis of native aortic valve.

OBJECTIVES: Balloon valvuloplasty (BV) before transcatheter aortic implantation has been thought to be mandatory before the valve is implanted. We have explored the feasibility and safety of direct implantation of balloon expandable Edwards SAPIEN XT valve without prior balloon dilatation. BACKGROUND: Some complications after transcatheter aortic valve replacement (TAVR) have been associated with unwanted effects of BV, mainly the contribution to stroke and severe aortic regurgitation (AR) before the valve is implanted. Direct implantation with a self-expanding aortic valve has been recently reported. METHODS: From November 2011 to April 2012, ten patients were selected that met the following criteria in the transesophageal echocardiography (TEE): moderate calcification, homogeneous distribution of calcium, symmetrical opening of the valve, and some degree of aortic insufficiency. RESULTS: All patients had symptomatic aortic stenosis of a native valve and high surgical risk; six patients had the valve mildly calcified, in four patients the degree of calcification was moderate. The native valve was crossed and the prosthetic aortic valve was properly positioned in all cases and implanted in the correct position. No patient underwent post-dilatation and trivial AR was present in four patients. There were no adverse events (death, need for pacemaker, myocardial infarction, or stroke). At 30 days post-procedure, all patients were alive and had significant clinical improvement. CONCLUSIONS: Direct implantation of Edwards SAPIEN XT without prior BV in selected cases is feasible and safe. The number of patients in whom this technique would be applicable, and their impact on reducing complications has to be determined.

Determinants of clinical improvement after surgical replacement or transcatheter aortic valve implantation for isolated aortic stenosis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement (SAVR) in patients with aortic stenosis (AS) and high surgical risk. Hemodynamic performance after TAVI is superior, but the impact of reverse remodeling on clinical improvement is controversial. We aim to address the differences in hemodynamic changes between SAVR and TAVI, and its correlation with LV remodeling and clinical improvement at 6 months follow-up. METHODS: Forty-two patients treated by TAVI were compared with 45 SAVR patients with a stented bioprosthesis. Clinical, 2D and 3D echocardiographic data were prospectively obtained before and six months after intervention. RESULTS: Patients had similar distribution for sex, body surface area and AS severity. TAVI patients were older, more symptomatic and had more comorbidities. They also had higher LV filling pressures, larger 3D indexed left atrium volume, but similar 3D indexed LV mass. At 6 months, TAVI patients had greater clinical improvement and higher effective orifice area index (EAOI), but only SAVR patients already had a significant decrease in 3D indexed LV mass and diastolic volume. In univariate analysis older age, NYHA class ≥ III, increase in EAOI and TAVI were related with functional class improvement. After multivariate analysis only NYHA class ≥ III (OR 8.81, CI:2.13-36.52; p=0.003) and an increase in EAOI ≥ 105% (OR 3.87, CI:1.02-14.70; p=0.04) were predictors of clinical improvement. CONCLUSIONS: At 6 months, functional class improvement was greater after TAVI. Higher initial NYHA class and an increase in EAOI ≥ 105% were independently associated with functional enhancement. It is debatable if left ventricular remodeling is determinant for functional class improvement.

Assessment of microcirculatory remodeling with intracoronary flow velocity and pressure measurements: validation with endomyocardial sampling in cardiac allografts.

BACKGROUND: Intracoronary physiology techniques have been validated extensively for the assessment of epicardial stenoses but not for the lone study of coronary microcirculation. We performed a comparison between 4 intracoronary physiological indices with the actual structural microcirculatory changes documented in transplanted hearts. METHODS AND RESULTS: In 17 cardiac allograft patients without coronary stenoses, ECG, intracoronary Doppler flow velocity, and aortic pressure were digitally recorded before and during maximal hyperemia with a dedicated system. Postprocessing of data yielded 4 indices of microcirculatory status: coronary flow velocity reserve (2.13+/-0.59), instantaneous hyperemic diastolic velocity pressure slope (2.33+/-1.25 cm x s x (-1)mm Hg(-1)), coronary resistance index (1.65+/-0.88 mm Hg x cm(-1) x s(-1)), and coronary resistance reserve (2.36+/-0.65). Quantitative morphometry was performed in endomyocardial biopsies during the same hospital intake; arteriolar obliteration (76.57+/-6.95%) and density (2.00+/-1.22 arterioles per 1 mm(2)) and capillary density (645+/-179 capillaries per 1 mm(2)) were measured. Univariate regression analysis between intracoronary measurements and histological findings revealed that instantaneous hyperemic diastolic velocity-pressure slope correlated with arteriolar obliteration (r=0.58, P=0.014) and capillary density (r=0.60, P=0.012). Statistical adjustment revealed an independent contribution of arteriolar obliteration (beta=0.61, P=0.0009) and capillary density (beta=-0.60, P=0.0008) to instantaneous hyperemic diastolic velocity-pressure slope values, resulting in an excellent predictive model (r=0.84, P=0.0002). Coronary resistance index correlated only with capillary density (r=0.70, P=0.019). Relative indices (coronary flow velocity reserve and coronary resistance reserve) did not correlate significantly with arteriolar obliteration, capillary density, or arteriolar density. CONCLUSIONS: Intracoronary indices derived from pressure and flow, particularly instantaneous hyperemic diastolic velocity-pressure slope, appear to be superior to coronary flow velocity reserve in detecting structural microcirculatory changes. Both arteriolar obliteration and capillary rarefaction seem to influence microcirculatory hemodynamics independently.

Sirolimus-eluting stents versus bare-metal stents in patients with in-stent restenosis: results of a pooled analysis of two randomized studies.

BACKGROUND: Treatment of patients with in-stent restenosis (ISR) remains a challenge. We sought to compare results of sirolimus-eluting stents (SES) with those of bare-metal stents (BMS) in patients with ISR. METHODS: The results obtained in the stent arm of two randomized studies were analyzed. The RIBS I study (450 patients with ISR) allocated 224 patients to BMS; the RIBS II study (150 patients with ISR) allocated 76 patients to SES. Complete 1-year follow-up was obtained in all 300 patients treated with stents. RESULTS: Although inclusion/exclusion criteria were identical in the two studies, when compared with patients in the BMS group, patients in the SES arm had more adverse baseline characteristics, more diffuse lesions, and smaller vessels. However, late angiographic findings including in-segment recurrent restenosis rate (11 vs. 38%, P < 0.001), minimal lumen diameter (2.52 vs. 1.63 mm, P < 0.001), and late loss (0.13 vs. 1.04 mm, P < 0.001) were significantly better after SES. The 1-year event-free survival was also significantly improved in the SES group (88 vs. 78%, P < 0.05), as the result of a lower requirement for repeated revascularizations (10.5 vs. 19.6%, P < 0.05). Prespecified subgroup analyses were consistent with the main outcome measures. After adjusting for (a) imbalances in baseline characteristics (restenosis OR 0.11 [95% confidence interval (CI) 0.03-0.36]; adverse events hazard ratios (HR) 0.33 [95% CI 0.13-0.84]) and (b) the propensity score (restenosis OR 0.08 [95% CI 0.03-0.28]; adverse events HR 0.24 [95% CI 0.09-0.66]), results of the SES group were superior to those obtained in the BMS group. CONCLUSIONS: When compared with BMS, SES improved the long-term clinical and angiographic outcome of patients with ISR.

Distortion of the terminal portion of the QRS is associated with poor collateral flow before and poor myocardial perfusion after percutaneous revascularization for myocardial infarction.

AIMS: The distortion of the terminal portion of the QRS has been related to adverse outcome in patients with ST-segment elevation myocardial infarction. METHODS: We studied the relationship of this electrocardiographic pattern with the angiographic findings in patients treated with percutaneous revascularization for ST-segment elevation myocardial infarction. We included 349 patients, 318 treated with primary angioplasty and 31 with rescue angioplasty after failed thrombolysis. RESULTS: Eighty-five patients were found with distortion of the terminal portion of the QRS complex (group 1) and 264 without it (group 2). Collateral flow was absent in 30 patients (35%) from group 1, versus 52 patients (20%) from group 2 [odds ratio (OR) 1.806, 1.097-2.974, P 0.019]. No-reflow occurred in 12 (14%) patients in group 1 versus 17 (6.4%) in group 2 (OR 2.388, 1.091-5.230, P 0.016). Myocardial perfusion was graded 2-3 in 28 patients (58%) of group 1 versus 98 (76%) in group 2 (OR 0.443, 0.220-0.893, P 0.021). CONCLUSION: Patients with ST-segment elevation myocardial infraction showing distortion of the terminal portion of the QRS have worse collateral flow, and present more often no-reflow or poor myocardial perfusion after percutaneous revascularization. These data contribute to explain the worse clinical outcome of these patients.

Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease.

Inhibition of the P2Y12 pathway by the platelet antagonist clopidogrel is associated with a marked reduction in platelet reactivity. Recent reports have shown that P2Y12 inhibition has anti-inflammatory effects as well. However, whether clopidogrel withdrawal is associated with proaggregatory and proinflammatory effects has not yet been explored. Since diabetic subjects are characterized by a prothrombotic and proinflammatory status, we hypothesize that these patients may be more vulnerable to these effects. A total 54 patients with diabetes on long-term (12 months) dual antiplatelet therapy (aspirin plus clopidogrel) were studied. Platelet aggregation (following 6 and 20 micromol/l ADP stimuli) and inflammatory markers (C-reactive protein and P-selectin expression) were assessed before and 1 month following clopidogrel withdrawal. Following clopidogrel withdrawal, aspirin responsiveness using platelet function analyzer-100 was determined as well. A significant increase in all the assessed platelet (P < 0.0001 for 6 and 20 micromol/l ADP-induced aggregation) and inflammatory (P < 0.05 for C-reactive protein, P < 0.001 for P-selectin expression in resting platelets, and P < 0.0001 for P-selectin expression in ADP-stimulated platelets) biomarkers was observed following clopidogrel withdrawal. Low responders to aspirin had increased platelet aggregation profiles (P < 0.05 for 6 and 20 micromol/l ADP-induced aggregation) but no differences in inflammatory markers. In conclusion, clopidogrel withdrawal is associated with an increase in platelet and inflammatory biomarkers in diabetic patients, supporting pleiotropic effects coupled with P2Y12 receptor antagonism.

Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.

OBJECTIVE: Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. METHODS AND RESULTS: The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation (P=0.025) and better responsiveness (P=0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P=0.025), increased platelet inhibition (P=0.006), and a more optimal drug response (P=0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. CONCLUSIONS: The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.

Usefulness of Drug-Eluting Balloons for Bare-Metal and Drug-Eluting In-Stent Restenosis (from the RIBS IV and V Randomized Trials).

Treatment of patients with drug-eluting stent (DES) in-stent restenosis (ISR) is particularly challenging. We sought to compare results of drug-eluting balloons in patients with DES-ISR with those in patients with bare-metal stent (BMS) ISR. A pooled analysis of the Restenosis Intra-Stent: Drug-Eluting Balloon versus Everolimus-Eluting Stent IV and V randomized trials was performed. Both trials had identical inclusion and exclusion criteria. Results of drug-eluting balloons in 95 patients with BMS-ISR and 154 patients with DES-ISR were compared. Patients with DES-ISR were more frequently diabetics, presented more often as an acute coronary syndrome and had more severe lesions and more frequently a focal pattern, including edge-ISR. Late angiographic findings (92% of eligible patients), including minimal lumen diameter (1.80 ± 0.6 vs 2.01 ± 0.6 mm, p = 0.001; absolute mean difference 0.21 mm; 95% confidence interval 0.04 to 0.38; p = 0.014) and restenosis rate (19% vs 9.5%, p <0.05) were poorer in DES-ISR. Results were consistent across 10 prespecified subgroups. Moreover, on multiple linear regression analysis, minimal lumen diameter at follow-up remained significantly smaller in patients with DES-ISR after adjusting for potential confounders (adjusted absolute mean difference 0.17 mm; 95% confidence interval 0.04 to 0.41; p = 0.019). Finally, at 1-year clinical follow-up (100% of patients), rates of target vessel revascularization (16% vs 6%, p = 0.02) and of the main combined clinical end point (18% vs 8%, p = 0.03) were significantly higher in patients treated for DES-ISR. In conclusion, this study confirms the efficacy of DEB for patients with ISR. However, the long-term clinical and angiographic results of DEB are poorer in patients with DES-ISR than in those with BMS-ISR. (ClinicalTrials.govIdentifier:NCT01239953&NCT01239940).

Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment.

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.

Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies.

OBJECTIVES: We compared the risk of stent thrombosis (ST) after drug-eluting stents (DES) versus bare-metal stents (BMS), and tested the hypothesis that the risk of DES thrombosis is related to stent length. BACKGROUND: Whether DES increase the risk of ST remains unclear. Given the very low restenosis rate after drug-eluting stenting, longer stents are frequently implanted for the same lesion length in comparison to BMS. METHODS: We included in a meta-analysis 10 randomized studies comparing DES and BMS. Overall, 5,030 patients were included (2,602 were allocated to DES and 2,428 to BMS). The risk of thrombosis after DES versus BMS was compared, and the relationship between the rate of DES thrombosis and stent length was evaluated. RESULTS: Incidence of ST was not increased in patients receiving DES (0.58% vs. 0.54% for BMS; odds ratio: 1.05; 95% confidence interval [CI]: 0.51 to 2.15; p = 1.000). The overall rate of ST did not differ significantly between patients receiving sirolimus- or paclitaxel-eluting stents (0.57% vs. 0.58%; p = 1.000). We found a significant relation between the rate of ST and the stented length (Y = -1.455 + 0.121 X; 95% CI for beta: 0.014 to 0.227; R = 0.716; p = 0.031). In patients with DES, mean stented length was longer in those suffering ST (23.4 +/- 8.1 mm vs. 21.3 +/- 4.1 mm, p = 0.025). CONCLUSIONS: Drug-eluting stents do not increase the risk of ST, at least under appropriate anti-platelet therapy. The risk of ST after DES implantation is related to stent length.

Long-term results (three to five years) of the Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study.

OBJECTIVES: We sought to analyze the very late outcomes of patients treated for in-stent restenosis (ISR) according to treatment allocation and 10 prespecified variables. BACKGROUND: Long-term results (>2 years) of patients with ISR undergoing repeat coronary interventions are not well established. METHODS: The Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study compared these two strategies in 450 patients with ISR. A detailed systematic protocol was used for late clinical follow-up. RESULTS: At one-year follow-up (100% of patients), the event-free survival was similar in the two groups (77% stent implantation [ST] arm, 71% balloon angioplasty [BA] arm, log-rank p = 0.19). Additional long-term clinical follow-up (median 4.3 years, range 3 to 5 years) was obtained in 98.6% of patients. During this time 22 additional patients died (9 ST arm, 13 BA arm), 7 suffered a myocardial infarction (3 ST arm, 4 BA arm), 23 required coronary surgery (11 ST arm, 12 BA arm), and 9 underwent repeat coronary interventions (4 ST arm, 5 BA arm) (nonexclusive events). At four years the event-free survival was 69% in the ST arm and 64% in the BA arm (log-rank p = 0.21). Among the 10 prespecified variables, vessel size > or = 3 mm had a major influence on the clinical outcome at four years, with better results in the ST group (hazard ratio 0.51, 95% confidence interval 0.3 to 0.89, p = 0.016). CONCLUSIONS: Patients with ISR undergoing repeat interventions have a significant event rate at late follow-up. Continued medical surveillance should be continued after one year. Patients with large vessels have a better outcome after repeat stenting.