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‘Plan S’ of Eleven research funders in Europe will make all scientific works free to read as soon as they are published – New policy if adopted could determine the Future of Global Journal Subscription as doomed

 

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/5/2018

On 5 November, the London-based Wellcome Trust and the Bill and Melinda Gates Foundation in Seattle, Washington, announced they were both endorsing ‘Plan S’, adding their weight to an initiative already backed by 13 research funders across Europe since its launch in September. The plan was spearheaded by Robert-Jan Smits, the European Commission’s special envoy on open access.

The Wellcome Trust, which gave out £1.1 billion (US$1.4 billion) in grants in 2016–17, is also the first funder to detail how it intends to implement Plan S. Its approach suggests that journals may not need to switch wholesale to open-access (OA) models by 2020 to be compliant with Plan S — if the initiative’s other backers decide on a similar line.

The biomedical charity already has an OA policy, but in some cases it allows an embargo of up to six months after publication before papers have to be made free to read. The organization says that by 1 January 2020, it will ban all such embargoes.

Wellcome-funded work will not be able to appear in NatureScience and other influential subscription journals unless these publications permit Wellcome-funded papers to be published under OA terms (Nature’s news team is editorially independent of its publisher, Springer Nature).

SOURCE

https://www.nature.com/articles/d41586-018-07300-5?utm_source=briefing-dy&utm_medium=email&utm_campaign=briefing&utm_content=20181105

 

Open Access Online Scientific Journal in Healthcare, Pharmaceuticals, MedTech, BioMed was launched by me in 4/2012, http://pharmaceuticalintelligence.com

  • Because I believe that scientific works must be free to read as soon as it is published !!!!

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In Nature 561, 17-18 (2018) doi: 10.1038/d41586-018-06178-7

Radical open-access plan could spell end to journal subscriptions – Eleven research funders in Europe announce ‘Plan S’ to make all scientific works free to read as soon as they are published.

04 SEPTEMBER 2018

Robert-Jan Smits, the European Commission’s special envoy on open access, spearheaded the Plan S initiative.Credit: Nikolay Doychinov/EU2018BG

Research funders from France, the United Kingdom, the Netherlands and eight other European nations have unveiled a radical open-access initiative that could change the face of science publishing in two years — and which has instantly provoked protest from publishers.

The 11 agencies, who together spend €7.6 billion (US$8.8 billion) in research grants annually, say they will mandate that, from 2020, the scientists they fund must make resulting papers free to read immediately on publication (see ‘Plan S players’). The papers would have a liberal publishing licence that would allow anyone else to download, translate or otherwise reuse the work. “No science should be locked behind paywalls!” says a preamble document that accompanies the pledge, called Plan S, released on 4 September.

“It is a very powerful declaration. It will be contentious and stir up strong feelings,” says Stephen Curry, a structural biologist and open-access advocate at Imperial College London. The policy, he says, appears to mark a “significant shift” in the open-access publishing movement, which has seen slow progress in its bid to make scientific literature freely available online.

As written, Plan S would bar researchers from publishing in 85% of journals, including influential titles such as Nature and Science. According to a December 2017 analysis, only around 15% of journals publish work immediately as open access (see ‘Publishing models’) — financed by charging per-article fees to authors or their funders, negotiating general open-publishing contracts with funders, or through other means. More than one-third of journals still publish papers behind a paywall, and typically permit online release of free-to-read versions only after a delay of at least six months — in compliance with the policies of influential funders such as the US National Institutes of Health (NIH).

And just less than half have adopted a ‘hybrid’ model of publishing, whereby they make papers immediately free to read for a fee if a scientist wishes, but keep most studies behind paywalls. Under Plan S, however, scientists wouldn’t be allowed to publish in these hybrid journals, except during a “transition period that should be as short as possible”, the preamble says.

Source: Universities UK

“Hybrid journals were always viewed as a step towards full open access. They haven’t succeeded as a transitionary measure,” says David Sweeney, who chairs Research England, one of the funding agencies subsumed under UKRI, the United Kingdom’s national research funder. The plan also states that funders will cap the amount they are willing to pay for open-access publishing fees, but doesn’t lay out what charge would be too much.

Putting the ‘s’ in Plan S

The initiative is spearheaded by Robert-Jan Smits, the European Commission’s special envoy on open access. (The ‘S’ in Plan S can stand for ‘science, speed, solution, shock’, he says). In addition to the French, British and Dutch funders, national agencies in Austria, Ireland, Luxembourg, Norway, Poland and Slovenia have also signed, as have research councils in Italy and Sweden.

“Paywalls are not only hindering the scientific enterprise itself but also they are an obstacle [to] the uptake of research results by the wider public,” says Marc Schiltz, president of Science Europe, a Brussels-based advocacy group that represents European research agencies and which officially launched the policy.

PLAN S PLAYERS

So far, 11 national funding agencies in Europe have signed up to Plan S.

  • Austrian Science Fund
  • French National Research Agency
  • Science Foundation Ireland
  • National Research Fund (Luxembourg)
  • Italian National Institute for Nuclear Physics
  • Netherlands Organisation for Scientific Research
  • Research Council of Norway
  • National Science Centre (Poland)
  • Slovenian Research Agency
  • Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning
  • UK Research and Innovation

Smits says he took inspiration from the open-access policy of the Bill & Melinda Gates Foundation, the global health charity based in Seattle, Washington, which also demands immediate open-access publishing. Because Plan S forbids hybrid publishing — and because it involves multiple funders — its impacts could be even more far-reaching than the Gates policy, which by itself has nudged several influential journals to change their publishing models.

Not quite all aboard

Despite Smits’ role, the European Commission hasn’t itself signed the plan. But Smits says that he expects the requirements to be integrated into the terms and conditions of future research grants from the commission. That hasn’t happened yet because policymakers are still debating the details of its next research and innovation programme, Horizon Europe, which begins in 2021 and will be worth €100 billion over 7 years. Smits says he expects more funding agencies to join, and that he will discuss the plan in the United States next month with White House officials, scientific academies and universities.

“The plan is roughly what one would want after about 15 years of funder experimentation with weaker policies,” says Peter Suber, director of the Harvard Open Access Project and the Harvard Office for Scholarly Communication in Cambridge, Massachusetts. “We are very supportive of the ambition set out in Plan S,” adds Jeremy Farrar, director of the Wellcome Trust, a large private biomedical charity in London. He says the funder is finalizing a new open-access policy.

But national research agencies in some of Europe’s leading scientific nations, such as Switzerland, Sweden and Germany, have not yet signed. In Sweden’s case, this is because it has doubts over the tight timetable, says Sven Stafström, head of the country’s research council. He says the council agrees with the aims of Plan S and will review its position on the document at a board meeting later this month. Peter Strohschneider, president of Germany’s national research council, the DFG, says his council hadn’t signed because of the way the plan mandates recipients of public funding to specific forms of open access. “We request our researchers to publish their findings from DFG grants open access but we do not mandate them,” he said. He also cautioned that if researchers were all told to publish in open-access journals, costs of publishing could increase.

Sweeney says that, in the United Kingdom, it isn’t possible to calculate how much funders will need to pay under open-access publishing without a fuller picture of how publishers will respond. “What it costs depends on the reaction of the industry. This is a statement about principles, it is not a statement about [publishing] models,” he says.

And for Stan Gielen, president of the Netherlands Organisation for Scientific Research (NWO), Plan S goes beyond the economics of publishing. “This is part of a bigger transition towards open science and a re-evaluation of how we measure science and the quality of scientists,” he says.

Publisher concerns

Asked for comments ahead of the plan’s launch, publishers said they had serious concerns — particularly around the banning of hybrid journals. A spokesperson for the International Association of Scientific, Technical and Medical Publishers (STM), based in Oxford, UK, which represents 145 publishers, told Nature’s news team that although it welcomed funders’ efforts to expand access to peer-reviewed scientific works, some sections of Plan S “require further careful consideration to avoid any unintended limitations on academic freedoms”. In particular, the STM spokesperson said, banning hybrid journals — which have delivered a lot of growth in open-access articles (see ‘Growth in open access’) — could “severely slow down the transition”. The publishing giant Elsevier said it supported the STM’s comments.

Source: UUK (2017)/BMC Med. 10, 124 (2012).

In another statement, a spokesperson for Springer Nature said: “Research, and the communication of it, is global. We urge research funding agencies to align rather than act in small groups in ways that are incompatible with each other, and for policymakers to also take this global view into account.” Removing publishing options from researchers “fails to take this into account and potentially undermines the whole research publishing system”, the statement added. (Nature’s news team is editorially independent of its publisher).

Meanwhile, the American Association for the Advancement of Science (AAAS), a non-profit organization that publishes the journal Science, said that the model outlined in Plan S “will not support high-quality peer-review, research publication and dissemination”. Implementing the plan would “be a disservice to researchers” and “would also be unsustainable for the Science family of journals”, the AAAS says.

Smits, however, says that it is essential that high-quality peer review remains part of the science publishing system under Plan S. “Publishers are not the enemy. I want them to be part of the change,” he says.

S for sanction?

Only a few funding agencies currently punish researchers who decide not to follow their open-access policies — including the Wellcome Trust and the NIH. But under Plan S, funders promise to “sanction non-compliance”, the initiative states. Smits suggests that a possible sanction for researchers who don’t comply could be withholding the final instalment of a grant, which is usually paid once a project is completed. But this, and other details such as the amount that funders are willing to pay to publish each article, will be worked out by the coalition in the run-up to 2020, he says.

Many European funders have been trying to make research free to read by brokering new ‘read-and-publish’ contracts with publishers, in which a single fee is paid to cover both the costs of reading paywalled research and of authors publishing under open-access terms. But some of the funders who have signed Plan S — including those in the Netherlands and Norway — now say they don’t intend to pay any more subscription fees beyond a transitionary period.

If other funders follow the Plan S idea, it could spell the end of scientific publishing’s dominant subscription business model, says John-Arne Røttingen, the head of Norway’s research council. “Subscription journals will see the opportunity to flip their business models into a system where what is paid for is the solid peer review, editorial reviewing and electronic dissemination of research results,” he says.

But Curry cautions that shifting from a subscription to an open-access business model around the world, as Plan S signers advocate, could bring a new challenge — how scientists in poorer nations will be able to afford to publish open-access work. “That has to be part of the conversation,” he says.

Nature 561, 17-18 (2018)

doi: 10.1038/d41586-018-06178-7
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Coronary Artery Interventions: Balloon, Stent, Drug-eluting Stent and Antiplatelet Demand

Curator: Justin D. Pearlman, MD, PhD, FACC

Italicized text represents the voice of Dr. Pearlman

Coronary Artery Disease (CAD), causing impeded blood supply to the heart, constitutes a major cause of disability and death, amounting to triple all forms of cancer combined. The warning symptoms may include a decline in exertion tolerance, usually accompanied by additional symptoms known as “chest pain.” However, “chest pain” is an inaccurate term because it may not be in the chest and it may not include pain (commonly, “chest pain” may occur in the neck, jaw, anterior chest and/or left arm, and may just felt as a light pressure, squeezing, ache, or sense of doom, sometimes with sweating, nausea and/or palpitations, the sensation of abnormal heart beats).

Dr. Heberden is credited with establishing the diagnostic malady called “angina pectoris.” Angina Pectoris corresponds to obstruction in a coronary artery resulting in  exertion-limiting symptoms related to effort (cardiac demand), typically in the chest, neck, jaw and/or arm. The term “angina pectoris” literally means sore throat in the chest. Classic angina is a pressure in the chest that moves to the left arm, reproducible at a particular degree of exertion, such as climbing 1 flight of stairs, that is relieved withing 5 minutes of rest or sublingual nitroglycerin. Other patterns of pain are called “atypical” either because they represent a different expression of the same disease, or because they are not cardiac in etiology. Many studies report that women with CAD are more often “atypical,” which can lead to missed diagnosis.

The first right heart catheterization in a human was performed by Werner Forssmann on himself in 1929. Diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s. Dr. Palin and others identified focal partial blockages in patients with angina by injecting the aorta with iodinated contrast agents followed by x-ray imaging. Selective coronary angiography was described by Mason Sones in the early 1960s, based on an accidental engagement of a catheter into a coronary origin during aortography. 

The facts that coronary angiography generally leads to intervention, and has some risk of damaging an artery and possibly triggering a heart attack, has promoted widespread use of “stress tests” to screen for risk level prior to consummating a decision to perform angiography for elevated coronary risk findings. Coronary revascularization has proven beneficial for classic “ST elevation” heart attacks or the equivalent presenting as a new left bundle block, within the first 6-12 hours of onset, preferably within 1 hour, and also for blockages with poor “flow reserve” involving all tree coronary territories or the left main coronary artery.  Also, revascularization provides a means to relieve angina as an alternative to medications for patients with lesser disease, even though that has not been shown to be reliable in prevention of future heart attacks. Some patients, particularly those with diffuse coronary disease not suitable for stents or bypass, undergo a repeated challenge of compression to the legs and buttocks called “EECP” (enhanced external couterpulsation) to stimulate natural remodeling of the blood supply to the heart, some, after severe damage substantially weakens the heart, take on the cancer and infection risks of a immunosuppression heart transplant, and some receive a mechanical heart or a left ventricular assist pump.

Whereas some “stress tests” check for “rush hour traffic jams” by checking status at baseline and then when speeding up the heart with an exercise challenge, other forms of “stress testing” use chemicals either to speed up the heart rate, to stimulate higher workload conditions, or just to increase blood flow in the coronary arteries (increase traffic by arterial dilation without stress).  Thus, just as “chest pain” does not have to include chest or pain, stress tests do not have to include stress.

Keywords: In-stent restenosis (ISR), stent thrombosis (ST), bare metal stents (BMS), drug-eluting stent (DES), drug-coated balloon (DCB), paclitaxel-eluting balloon (PEB)

The history of cardiac catheterization. – NCBI

Can J Cardiol. 2005 Oct;21(12):1011-4.

The history of cardiac catheterization.

Abstract

The evolution of cardiac catheterization has occurred over at least four centuries. One of the first major steps was the description of the circulation of the blood by William Harvey in 1628. The next milestone was the measurement of arterial pressure by Stephen Hales, one century later. The 19th century represented the golden age of cardiovascular physiology, highlighted by the achievements of Carl Ludwig (physiology of blood pressure), Etienne-Jules Marey (pulse and blood pressure measurement) and Claude Bernard (vasomotor control of blood supply), among others. Human cardiac catheterization developed during the 20th century. The first right heart catheterization in a human was performed by Werner Forssmann on himself in 1929. Diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s, and selective coronary angiography was described by Mason Sones in the early 1960s. More recently, with the advent of catheter-based interventions, pioneered by Andreas Gruentzig in the late 1970s, there has been considerable progress in the refinement and expansion of these techniques. Currently, the Sones technique (direct cannulation of a coronary artery) substantially replaced the previously indirect aortography coronary angiography. Both selective coronary angiography and percutaneous coronary intervention rely mainly on percutaneous femoral and percutaneous radial artery entry routs.

On the occasion of the 50th anniversary of the Montreal Heart Institute, we will highlight the contributions of that institution on selective coronary angiography and percutaneous coronary interventions.

PMID:
16234881

https://www.uptodate.com/contents/intracoronary-stent-restenosis

 

Etiopathogenesis

Restenosis is a progressive phenomenon that begins in the early hours after the barotrauma from PCI (Table 1).

Table 1

Time-related assessment of in-stent restenosis (ISR)
Early (within days)
   Elastic return (recoil) (ER)
   Relocation of axially transmitted plaque
Late (weeks to months)
   Reorganization of thrombus
   Neointima formation
      Cell proliferation
      Cell migration
      Cell matrix synthesis
   Remodelling
   Resolution of inflammation

ISR, in-stent restenosis; ER, elastic recoil.

The three major pathogenic mechanisms that underlie restenosis are:

  1. Early elastic return (recoil) (ER);
  2. Vascular remodeling;
  3. Neointimal hyperplasia.

The first and the second mechanisms are typical of “old-style” or “plain old balloon” angioplasty (POBA) before the stent era. The presence of metallic struts from stents promotes a new mechanism called neointimal hyperplasia.

Myointimal trauma induced by PCI affects the atherosclerotic process and changes its course from the natural evolution of atherosclerotic plaque to a more aggressive local response to the treatment. Atherosclerosis is characterized by a sequence of processes which induce vasoconstriction and the initial endothelial dysfunction resulting in the mechanism of endoplasmic reticulum (ER and vascular remodelling, enhanced by an inflammatory process triggered by vessel injury, as evidenced by the increase in C-reactive protein or MCP-1 in patients at increased risk of restenosis (20).

SOURCES

 

 

The following articles review the benefits of stents to keep coronary arteries propped open after balloon expansion of a focal area of blockage. These articles establish the motivation for drug-eluting stents to address the problem that stents introduced of stimulating a tissue reaction which causes early in-stent re-stenosis (tissue in-growth obstructing the desired blood channel).

Research findings which support the widespread use of drug-eluting stents and uninterrupted use of strong antiplatelet agents

  • TI In-stent restenosis in the drug-eluting stent era.
  • AU Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R
  • SO J Am Coll Cardiol. 2010;56(23):1897.
The introduction of the drug-eluting stent (DES) proved to be an important step forward in reducing rates of restenosis and target lesion revascularization after percutaneous coronary intervention. However, the rapid implementation of DES in standard practice and expansion of the indications for percutaneous coronary intervention to high-risk patients and complex lesions also introduced a new problem: DES in-stent restenosis (ISR), which occurs in 3% to 20% of patients, depending on patient and lesion characteristics and DES type. The clinical presentation of DES ISR is usually recurrent angina, but some patients present with acute coronary syndrome. Mechanisms of DES ISR can be biological, mechanical, and technical, and its pattern is predominantly focal. Intravascular imaging can assist in defining the mechanism and selecting treatment modalities. Based upon the current available evidence, an algorithm for the treatment approaches to DES restenosis is proposed.AD
Cardiovascular Institute, Mount Sinai Medical Center, New York, New York 10029, USA. george.dangas@mssm.eduPMID
This is an early report on advantages of stent placement over the prior “plain old balloon angioplasty” (POBA). 
BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes.
METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.
RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, P = 0.011), a larger immediate increase in the diameter of the lumen (1.72 +/- 0.46 vs. 1.23 +/- 0.48 mm, P<0.001), and a larger luminal diameter immediately after the procedure (2.49 +/- 0.43 vs. 1.99 +/- 0.47 mm, Por = 50 percent) of 22 and 32 percent, respectively (P = 0.02). Peripheral vascular complications necessitating surgery, blood transfusion, or both were more frequent after stenting than after balloon angioplasty (13.5 vs. 3.1 percent, P<0.001). The mean hospital stay was significantly longer in the stent group than in the angioplasty group (8.5 vs. 3.1 days, Por =50% follow-up diameter stenosis [DS]) in 419 of 1,437 (29%) patients undergoing routine angiographic follow-up correlated directly with the likelihood of TLR (73% vs. 26% for>70% DS compared with<60% DS). Smaller pretreatment minimum lumen diameter (MLD), smaller final MLD, longer stent length, diabetes mellitus, unstable angina, and hypertension were independent predictors of TLR. Prior MI and current smoking were negative predictors.
CONCLUSIONS: At one year after stenting, most clinical restenosis reflected TLR, which was predicted by the same variables previously associated with an increased risk of angiographic restenosis. The lower absolute rate of clinical restenosis relative to angiographic restenosis was due to infrequent TLR in lesions with less severe (28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization.
CONCLUSION: Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents.

The following reports clarified the basis for early stent re-stenosis, first by intravascular miniaturized ultrasound imaging of the problem, then by animal models.

BACKGROUND: Studies have suggested that restenosis within Palmaz-Schatz stents results from neointimal hyperplasia or chronic stent recoil and occurs more frequently at the articulation.
METHODS AND RESULTS: Serial intravascular ultrasound (IVUS) was performed after intervention and at follow-up in 142 stents in 115 lesions. IVUS measurements (external elastic membrane [EEM], stent, and lumen cross-sectional areas [CSAs]and diameters) were performed, and plaque CSA (EEM lumen in reference segments and stent lumen in stented segments), late lumen loss (delta lumen), remodeling (delta EEM in reference segments and delta stent in stented segments), and tissue growth (delta plaque) were calculated. After intervention, the lumen tended to be smallest at the articulation because of tissue prolapse. At follow-up, tissue growth was uniformly distributed throughout the stent; the tendency for greater neointimal tissue accumulation at the central articulation reached statistical significance only when normalized for the smaller postintervention lumen CSA. In stented segments, late lumen area loss correlated strongly with tissue growth but only weakly with remodeling. Stents affected adjacent vessel segments; remodelingprogressively increased and tissue growth progressively decreased at distances from the edge of the stent. These findings were similar in native arteries and saphenous vein grafts and in lesions treated with one or two stents. There was no difference in the postintervention or follow-up lumen (at the junction of the two stents) when overlapped were compared with nonoverlapped stents.
CONCLUSIONS: Late lumen loss and in-stent restenosis were the result of neointimal tissue proliferation, which tended to be uniformly distributed over the length of the stent.

Animal modeling as well as human sample histology showed biochemical basis for stent tissue in-growth which lead to effective choices for drug-eluting stents to release chemicals slowly over a long time to counteract that issue. However, the treatment may be too effective, as it also blocks protective endothelial lining of the stents, so blood products in circulation passing through a stent remain exposed to trauma that can promote thrombosis.

OBJECTIVES: We examined the relative contributions of inflammation and arterial injury to neointimal formation in a porcine coronary overstretch restenosis model.
BACKGROUND: Previous studies established that stents cause neointimal proliferation proportional to injury. Although inflammation has been postulated to be a major contributor to restenosis after angioplasty, there is a paucity of data on the relation between inflammation and subsequent neointimal formation.
METHODS: Twenty-one pigs underwent balloon injury followed by implantation of oversized, tubular, slotted stents (stent/artery ratio 1.2:1) in the left anterior descending coronary artery. Morphometric analysis of the extent of injury (graded as injury score 0 to 3) and inflammation (graded as inflammation score 0 to 3) 1 month later was assessed and correlated with neointimal formation.
RESULTS: An inflammatory reaction was observed in 20 of 21 pigs, and significant positive correlations were found between the degree of arterial injury and the extent of the inflammatory reaction (r = 0.80, p<0.01) and between the extent of inflammatory reaction and the neointimal thickness (r = 0.75, p<0.01), neointimal area (r = 0.53, p = 0.01) and percent area stenosis (r = 0.66, p<0.01) within the stents. Importantly, there were areas with inflammation only in the absence of injury, and vice versa, that were also associated with neointimal hyperplasia.
CONCLUSIONS: These data suggest that the inflammatory reaction plays an equally important role as arterial injury in neointimal formation after coronary stenting, and that anti-inflammatory approaches may be of value to reduce in-stent restenosis.

BACKGROUND: Experimental animal studies have shown that coronary stenting induces neointimal proliferation. However, the histopathological events after coronary stenting in humans have not been studied systematically.
METHODS AND RESULTS: We investigated 11 stented coronary arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link stent) obtained from 11 patients who had died 2 days to 21 months after stenting. We focused on gross, histological, and immunohistochemical aspects of the repair processes. Two patients developed symptoms of restenosis. Serial sections were stained with antibodies against smooth muscle cells (SMCs), macrophages, and endothelial cells. At 9 and 12 days after stenting, the stent sites showed thrombus formation with early formation of neointima composed of abundant macrophages and alpha-actin-negative spindle cells. From 64 days on, all sites with stenting showed a distinct layer of neointima, albeit to varying degrees. In nonrestenotic lesions, neointimal thickening was markedly less than in restenotic lesions but without qualitative differences; the neointima contained macrophages but was composed predominantly of alpha-actin-positive SMCs.
CONCLUSIONS: These observations strongly support the concept that neointimal proliferation in humans is a process of staged redifferentiation of SMCs, which may cause in-stent stenosis. Moreover, the exuberant neointimal proliferation with accumulation of macrophages and extensive neovascularization at sites of stent restenosis suggests a role for organization of mural thrombus.

BACKGROUND: Despite the increasing use of stents, few reports have described human coronary artery morphology early and late after stenting.

METHODS AND RESULTS: Histology was performed on 55 stents in 35 coronary vessels (32 native arteries and 3 vein grafts) from 32 patients. The mean duration of stent placement was 39+/-82 days. Fibrin, platelets, and neutrophils were associated with stent struts</=11 days after deployment. In stents implanted for20 associated inflammatory cells compared with 44% of struts embedded in a lipid core and 36% of struts in contact with damaged media (P<0.001). Neointimal growth determined late histological success, and increased neointimal growth correlated with increased stent size relative to the proximal reference lumen area. Neointimal thickness was greater for struts associated with medial damage than struts in contact with plaque (P<0.0001) or intact media (P<0.0001). When matched for time since treatment, neointimal cell density in stented arteries was similar to that in unstented arteries that had undergone balloon angioplasty and showed similar proteoglycan deposition.

CONCLUSIONS: Morphology after coronary stenting demonstrates early thrombus formation and acute inflammation followed by neointimal growth. Medial injury and lipid core penetration by struts result in increased inflammation. Neointima increases as the ratio of stent area to reference lumen area increases. Deployment strategies that reduce medial damage and avoid stent oversizing may lower the frequency of in-stent restenosis.

OBJECTIVES: The goal of this study was to evaluate the cellular and extracellular composition of human coronary arterial in-stent restenosis after various periods of time following stent deployment.

BACKGROUND: Neointimal in-growth rather than stent recoil is thought to be important for coronary arterial in-stent restenosis. There is only limited data on the cellular and extracellular composition changes with time after stent deployment.

METHODS: We analyzed 29 coronary arterial in-stent restenotic tissue samples (14 left anterior descending coronary artery, 10 right coronary artery, and 5 left circumflex artery) retrieved by using directional coronary atherectomy from 25 patients at 0.5 to 23 (mean, 5.7) months after deployment of Palmaz-Schatz stents employing histochemical and immunocytochemical techniques.

RESULTS: Cell proliferation was low (0% to 4%). Myxoid tissue containing extracellular matrix (ECM) enriched with proteoglycans was found in 69% of cases and decreased over time after stenting. Cell-depleted areas were found in 57% of cases and increased with time after stenting. Versican, biglycan, perlecan, and hyaluronan were present with varying individual distributions in all samples. Positive transforming growth factor-beta1 staining was found in 80% of cases. Immunostaining with alpha-smooth muscle actin identified the majority of cells as smooth muscle cells with occasional macrophages present (<or =12 cells per section).

CONCLUSIONS: These data suggest that enhanced ECM accumulation rather than cell proliferation contribute to later stages of in-stent restenosis. Balloon angioplasty of in-stent restenosis may, therefore, fail due to ECM changes during: 1) additional stent expansion, 2) tissue extrusion out of the stent, or 3) tissue compression.

BACKGROUND: Coronary-artery stents are known to reduce rates of restenosis after coronary angioplasty, but it is uncertain how long this benefit is maintained.

METHODS: We evaluated clinical and angiographic follow-up information for up to three years after the implantation of Palmaz-Schatz metallic coronary-artery stents in 143 patients with 147 lesions of native coronary arteries.

RESULTS: The rate of survival free of myocardial infarction, bypass surgery, and repeated coronary angioplasty for stented lesions was 74.6 percent at three years. After 14 months, revascularization of the stented lesion was necessary in only three patients (2.1 percent). In contrast, coronary angioplasty for a new lesion was required in 11 patients (7.7 percent). Follow-up coronary angiography of 137 lesions at six months, 114 lesions at one year, and 72 lesions at three years revealed a decrease in minimal luminal diameter from 2.54 +/- 0.44 mm immediately after stent implantation to 1.87 +/- 0.56 mm at six months, but no further decrease in diameter at one year (in patients with paired angiograms, 1.95 +/- 0.49 mm at both six months and one year). Significant late improvement in luminal diameter was observed at three years (in patients with paired angiograms, 1.94 +/- 0.48 mm at six months and 2.09 +/- 0.48 mm at three years; P<0.001).

CONCLUSIONS: Clinical and angiographic outcomes up to three years after coronary-artery stenting were favorable, with a low rate of revascularization of the stented lesions. Late improvement in luminal diameter appears to occur between six months and three years.

BACKGROUND: Recently, it has been reported that the luminal diameter shows phasic changes after stenting: the progression of luminal narrowing followed by its regression. To elucidate the mechanisms involved in the phasic changes in luminal diameter after stenting, we examined the changes in neointimal thickness and the appearance of neointima by a series of angiographic and angioscopic observations for 3 years after stent implantation.

METHODS AND RESULTS: In 12 patients who received a Wiktor coronary stent, serial angiographic and angioscopic examinations were performed immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after the stenting without repetition of angioplasty. Neointimal thickness was determined by angiography as the difference between stent and luminal diameters. The angioscopic appearance of neointima over the stent was classified as transparent or nontransparent according to the visibility of the majority of the stent. Neointimal thickness increased significantly at 3 months (0.75+/-0.32 mm) without further changes at 6 months (0.74+/-0.32 mm). Thereafter, however, it decreased significantly over 3 years (0.51+/-0.26 mm). The angioscopic appearance was classified as transparent in 8 patients (100) immediately after stenting, 6 patients (100%) at 2 to 4 weeks, 2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7 patients (58%) at 3 years.

CONCLUSIONS: The neointima became thick and nontransparent until 6 months and then became thin and transparent by 3 years. We conclude that neointimal remodeling exists after stenting and plays a major role in the alteration of coronary luminal diameter after stenting.

Although previous randomized trials 1-2 have demonstrated lower restenosis rates in selected lesions with coronary stents than with conventional balloon angioplasty. in-stent restenosis remains an important clinical problem.(3,4) Previous serial angiographic studies(5,6) showed that lumen loss after stenting occurred within 6 months. On the other hand, improvements in lumen dimensions between 6 months and 2 to 3 years have been demonstrated by angiography.(6-9) Serial (postintervention and at 6-month follow-up) intravascular ultrasound (IVUS) studies(10,11) have demonstrated that coronary stenting eliminates negative arterial remodeling, and thus intimal hyperplasia is solely responsible for in-stent restenosis. However, little has been reported about changes in intimal hyperplasia that occur beyond this 6-month period. This serial IVUS study evaluated the changes in intimal hyperplasia between 6 and 12 months after stent placement.

BACKGROUND: The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR).

METHODS AND RESULTS: We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (10 mm within the stent, pattern III includes ISR>10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively; P=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (P=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (Por =50%, late lumen loss as lumen diameter reduction and target lesion revascularization (TLR) as any repeat PTCA or coronary artery bypass surgery involving the stented lesion.

RESULTS: Multivariate analysis demonstrated that diabetes mellitus, placement of multiple stents and minimal lumen diameter (MLD) immediately after stenting were the strongest predictors of restenosis. Diabetes increased the risk of binary restenosis with an odds ratio (OR) [95% confidence interval]of 1.86 [1.56 to 2.16]and the risk of TLR with an OR of 1.45 [1.11 to 1.80]. Multiple stents increased the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06]and that of TLR with an OR of 1.94 [1.66 to 2.22]. An MLDor = 50% diameter stenosis at follow-up angiography, diffuse restenosis as a follow-up lesion length>or = 10 mm and aggressive restenosis as either an increase in lesion length from the original lesion or a restenotic narrowing tighter than the original. Clinical, anatomic and procedural characteristics were evaluated for lesions associated with these types of restenosis.

RESULTS: Diffuse restenosis was associated with a smaller reference artery diameter, longer lesionlength, female gender, longer stent length and the use of coil stents. Aggressive restenosis was more common in women, with the use of Wallstents and with long stent to lesion length ratios. Aggressive restenosis occurred earlier and was more closely associated with symptoms and myocardial infarctions than nonaggressive restenotic lesions.

CONCLUSIONS: Markers for diffuse restenosis were also important markers for the presence of any restenosis. A long stent to lesion length ratio is an important marker for aggressive restenosis. When severe forms of in-stent restenosis occur, they tend to present earlier and with more symptoms, including myocardial infarction. More careful consideration of the type of in-stent restenosis may aid in identifying when alternative strategies may be useful.

OBJECTIVES: We sought to assess whether coronary stents have modified the predictive value of demographic, clinical and quantitative coronary angiographic (QCA) predictors of coronary restenosis.

BACKGROUND: A systematic analysis in a large cohort of registries and randomized trials of the percutaneous transluminal coronary angioplasty (PTCA) and stent era has never been performed.

METHODS: A total of 9,120 treated lesions in 8,156 patients included in nine randomized trials and 10 registries, with baseline, post-procedural and six-month follow-up QCA analyses, were included in this study. Predictors of restenosis were identified with univariate and multivariate logistic regression analyses. Interaction terms were introduced in the regression equation to evaluate whether the predictors of restenosis were common to both eras or specific for either one of the revascularization techniques.

RESULTS: The restenosis rate was 35% after PTCA and 19% after angioplasty with additional stenting. In the univariate analysis, favorable predictors were previous coronary artery bypass graft surgery (CABG), stent use, stent length and a large pre-procedural minimal lumen diameter (pre-MLD); unfavorable predictors were weight, body mass index, diabetes mellitus, multi-vessel disease, lesion length and a high residual post-procedural diameter stenosis (post-DS). Predictors specific for the PTCA population were a large post-procedural MLD (post-MLD) as favorable and a severe pre-procedural DS (pre-DS) as unfavorable. Favorable predictors specific for the stent population were a large post-MLD and a large pre-procedural reference diameter (pre-RD). In the multivariate analysis, the best model included the following favorable predictors: stent use, a large post-MLD, previous CABG and the interaction term between stent use and a large post-MLD; unfavorable predictors were lesion length and diabetes mellitus.

CONCLUSIONS: There are no major differences in demographic and clinical predictors of coronary restenosis between PTCA and stent populations. In the modern (stent) era, a severe pre-DS is no longer an unfavorable predictor of restenosis. Still important, but more so in the stent population, is a large post-MLD (optimal result). Finally, a larger pre-RD became a favorable predictor with the advent of stenting.

OBJECTIVES: We sought to evaluate the relation between stented segment length and restenosis.

BACKGROUND: Multiple or long coronary stents are now being implanted in long lesions or in tandem lesions. A longer stented segment might result in a higher probability of restenosis. However, there is little information available on the relation between stented segment length and restenosis.

METHODS: Between April 1995 and December 1996, 725 patients with 1,090 lesions underwent stenting. Lesions were divided into three groups according to the length of the stented segment: 1) group I (n = 565): stented segment length20 but35 mm.

RESULTS: There was no significant difference in the incidence of subacute stent thrombosis among the three groups (0.4% in group I, 0.4% in group II, 1.2% in group III; p = NS). The minimal lumen diameter (MLD) after stenting was greater in group I than in group III (3.04 +/- 0.60 mm in group I, 3.01 +/- 0.54 mm in group II, 2.91 +/- 0.58 mm in group III; p<0.05). At follow up, a smaller MLD was observed in group III as compared with group I and group II (2.04 +/- 0.93 mm in group I, 1.92 +/- 1.00 mm in group II, 1.47 +/- 0.97 mm in group III; p<0.01). The restenosis rates were 23.9% in group I, 34.6% in group II and 47.2% in group III (p36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to11.01; P<0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P<0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P=0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P<0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P=0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P<0.01).

CONCLUSIONS: Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

BACKGROUND: The aim of this study was to evaluate the relationship between residual plaque burden after coronary stent implantation and the development of late in-stent neointimal proliferation.

METHODS AND RESULTS: Between January 1996 and May 1997, 50 patients underwent intravascular ultrasound (IVUS) interrogation at 6+/-1.2 months after coronary stent implantation in native coronary arteries. IVUS images were acquired with a motorized pullback, and cross-sectional measurements were performed within the stents at 1-mm intervals. The following measurements were obtained: (1) lumen area (LA), (2) stent area (SA), (3) area delimited by the external elastic membrane (EEMA), (4) percent neointimal area calculated as (SA-LA/SA)x100, and (5) percent residual plaque area calculated as (EEMA-SA)/EEMAx100. Volume measurements within the stented segments were calculated by applying Simpson’s rule. In the pooled data analysis of 876 cross sections, linear regression showed a significant positive correlation between percent residual plaque area and percent neointimal area (r=0.50, y= 45.03+0.29x, P<0.01). There was significant incremental increase in mean percent neointimal area for stepwise increase in percent residual plaque area. Mean percent neointimalarea was 16.3+/-10.3% for lesions with a percent residual plaque area of/=50% (P<0.001). The volumetric analysis showed that the percent residual plaque volume was significantly greater in restenotic lesions compared with nonrestenotic lesions (58.7+/-4.3% versus 51.4+/-5.7%, respectively; Por = 50% diameter stenosis at follow-up, follow-up percent diameter stenosis [DS]and follow-up minimal lumen diameter [MLD]) were determined.

RESULTS: Three variables were the most consistent predictors of the follow-up angiographic findings: ostial lesion location, IVUS preinterventional lesion site plaque burden (plaque/total arterial area) and IVUS assessment of final lumen dimensions (whether final lumen area or final MLD). All three variables predicted both the primary (binary restenosis) and secondary (follow-up MLD and follow-up DS) end points. In addition, a number of variables predicted one or more but not all the end points: 1) restenosis (IVUS preinterventional lumen and arterial area); 2) follow-up DS (QCA lesion length); and 3) follow-up MLD (QCA lesion length and preinterventional MLD and DS and IVUS preinterventional lumen and arterial area).

CONCLUSIONS: Ostial lesion location and IVUS preinterventional plaque burden and postinterventional lumen dimensions were the most consistent predictors of angiographic in-stent restenosis.

OBJECTIVES: We aimed to identify periprocedural quantitative coronary angiographic (QCA) variables that have predictive value on long-term angiographic results and to construct multivariate models using these variables for postprocedural prognosis.

BACKGROUND: Coronary stent implantation has reduced the restenosis rate significantly as compared with balloon angioplasty in short de novo lesions in coronary arteries>3 mm in size. Although the postprocedural minimal luminal diameter (MLD) is known to have significant bearing on long-term angiographic results, no practically useful model exists for prediction of angiographic outcome based on the periprocedural QCA variables.

METHODS: The QCA data from patients who underwent Palmaz-Schatz stent implantation for short (3 mm and completed six months of angiographic follow-up in the four prospective clinical trials (BENESTENT I, BENESTENT II pilot, BENESTENT II and MUSIC) were pooled. Multiple models were constructed using multivariate analysis. The Hosmer-Lemeshow goodness-of-fit test was used to identify the model of best fit, and this model was used to construct a reference chart for prediction of angiographic outcome on the basis of periprocedural QCA variables.

RESULTS: Univariate analysis performed using QCA variables revealed that vessel size, MLD before and after the procedure, reference area before and after the procedure, minimal luminal cross-sectional area before and after the procedure, diameter stenosis after the procedure, area of plaque after the procedure and area stenosis after the procedure were significant predictors of angiographic outcome. Using multivariate analysis, the Hosmer-Lemeshow goodness-of-fit test showed that the model containing percent diameter stenosis after the procedure and vessel size best fit the data. A reference chart was then developed to calculate the expected restenosis rate.

CONCLUSIONS: Restenosis rate after stent implantation for short lesions can be predicted using the variables percent diameter stenosis after the procedure and vessel size. This meta-analysis indicates that the concept of “the bigger the better” holds true for coronary stent implantation. Applicability of the model beyond short lesions should be tested.

BACKGROUND: Restenosis prediction from published studies is hampered by inadequate sample size and incomplete angiographic follow-up. The prediction of restenosis with the existing variables is poor. The aim of the present study was to include the clinical and angiographic variables commonly associated with angiographic restenosis and develop a prediction model for restenosis from the PRESTO database.

METHODS AND RESULTS: This study included 1312 patients with a single lesion enrolled in the angiographic substudy of the PRESTO trial. We constructed 2 risk scores. The first used preprocedural variables (female gender, vessel size [4 mm], lesion length>20 mm, diabetes, smoking status, type C lesion, any previous percutaneous coronary intervention [PCI], and unstable angina) derived from previous studies. Estimated restenosis rates and corresponding variability for each possible level of the resultant risk score were obtained via bootstrapping techniques. The area under the receiver-operator characteristic (ROC) curve was 0.63, indicating modest discriminatory abilityto predict restenosis. The second approach constructed a multiple logistic regression model considering significant univariate clinical and angiographic predictors of restenosis identified from the PRESTO database (treated diabetes mellitus, nonsmoker, vessel size, lesion length, American College of Cardiology/American Heart Association type C lesion, ostial location, and previous PCI). The area under the ROC curve for this risk score was also 0.63.

CONCLUSIONS: The preprocedural clinical and angiographic variables from available studies and from the PRESTO trial have only modest predictive ability for restenosis after PCI.

  • AD Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn 55905, USA.
  • PMID 15173022
  • TI Effects of stent length and lesion length on coronary restenosis.
  • AU Mauri L, O’Malley AJ, Cutlip DE, Ho KK, Popma JJ, Chauhan MS, Baim DS, Cohen DJ, Kuntz RE
  • SO Am J Cardiol. 2004;93(11):1340.

The choice of drug-eluting versus bare metal stents is based on costs and expectations of restenosis and thrombosis risk. Approaches to stent placement vary from covering just the zone of maximal obstruction to stenting well beyond the lesion boundaries (normal-to-normal vessel). The independent effects of stented lesion length, nonstented lesion length, and excess stent length, on coronary restenosis have not been evaluated for bare metal or drug-eluting stents. We analyzed the angiographic follow-up cohort (1,181 patients) from 6 recent bare metal stent trials of de novo lesions in native coronary arteries. Stent length exceeded lesion length in 87% of lesions (mean lesion length 12.4 +/- 6.3 mm, mean stent length 20.0 +/- 7.9 mm, mean difference 7.6 +/- 7.9 mm). At 6- to 9-month follow-up, the mean percent diameter stenosis was 39.1 +/- 20.1%. In an adjusted multivariable model of percent diameter stenosis, each 10 mm of stented lesion length was associated with an absolute increase in percent diameter stenosis of 7.7% (p<0.0001), whereas each 10 mm of excess stent length independently increased percent diameter stenosis by 4.0% (p<0.0001) and increased target lesion revascularization at 9 months (odds ratio 1.12, 95% confidence interval 1.02 to 1.24). Significant nonstented lesion length was uncommon (12.5% of cases). In summary, stent length exceeded lesion length in most stented lesions, and the amount of excess stent length increased the risk of restenosis independent of the stented lesion length. This analysis supports a conservative approach of matching stent length to lesion length to reduce the risk of restenosis with bare metal stents.

BACKGROUND: Observed rates of restenosis after drug-eluting stenting are low (or =32% relative increase in power,>or =24% absolute increase for late loss between 0.2 and 0.6 mm).

CONCLUSIONS: Late loss is monotonically related to restenosis risk in published stent trials. It is a generalizable and powerful angiographic end point in early or small trials of new drug-eluting stents.

BACKGROUND: Binary angiographic and clinical restenosis rates can vary widely between clinical studies, even for the same stent, influenced heavily by case-mix covariates that differ among observational and randomized trials intended to assess a given stent system. We hypothesized that mean in-stent late loss might be a more stable estimator of restenosis propensity across such studies.

METHODS AND RESULTS: In 46 trials of drug-eluting and bare-metal stenting, increasing mean late loss was associated with higher target lesion revascularization (TLR) rates (P<0.001). When the class of bare-metal stents was compared with the class of effective drug-eluting stents, late loss was more discriminating than TLR as measured by the high intraclass correlation coefficient (rho) (late loss, rho=0.71 versus TLR, rho=0.22; 95% CI of difference=0.33, 0.65). When the individual drug-eluting stents and bare-metal stents were compared, late loss was a better discriminator than TLR (0.68 versus 0.19; 95% CI of difference=0.24, 0.60). Greater adjustments of study covariates are needed to stabilize assessments of TLR compared with late loss because of greater influence of reference vessel diameter on TLR than on in-stent late loss. Optimization of late loss with the use of a novel method ofstandardization according to diabetes prevalence and mean lesion length resulted in minor adjustments in late loss (<0.08 mm for 90% of reported trials) and an ordered array of mean late loss values for the stent systems studied.

CONCLUSIONS: Late loss is more reliable than restenosis rates for discriminating restenosis propensity between new drug-eluting stent platforms across studies and might be the optimum end point for evaluating drug-eluting stents in early, nonrandomized studies.

BACKGROUND: Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization.

METHODS: We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days.

RESULTS: The rate of failure of the target vessel was reduced from 21.0 percent with a standard stentto 8.6 percent with a sirolimus-eluting stent (P<0.001)–a reduction that was driven largely by a decrease in the frequency of the need for revascularization of the target lesion (16.6 percent in the standard-stent group vs. 4.1 percent in the sirolimus-stent group, P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received sirolimus-eluting stents, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target-lesion revascularization in all subgroups examined.

CONCLUSIONS: In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed.

  • AD Cardiovascular Research Foundation and Lenox Hill Heart and Vascular Institute of New York, New York 10021, USA. jmoses@lenoxhill.net
  • PMID 14523139
  • TI A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.
  • AU Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME, TAXUS-IV Investigators
  • SO N Engl J Med. 2004;350(3):221.

BACKGROUND: Restenosis after coronary stenting necessitates repeated percutaneous or surgical revascularization procedures. The delivery of paclitaxel to the site of vascular injury may reduce the incidence of neointimal hyperplasia and restenosis.

METHODS: At 73 U.S. centers, we enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis (vessel diameter, 2.5 to 3.75 mm; lesion length, 10 to 28 mm) in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a bare-metal stent, and 662 to receive an identical-appearing, slow-release, polymer-based, paclitaxel-eluting stent. Angiographic follow-up was prespecified at nine months in 732 patients.

RESULTS: In terms of base-line characteristics, the two groups were well matched. Diabetes mellitus was present in 24.2 percent of patients; the mean reference-vessel diameter was 2.75 mm, and the mean lesion length was 13.4 mm. A mean of 1.08 stents (length, 21.8 mm) were implantedper patient. The rate of ischemia-driven target-vessel revascularization at nine months was reduced from 12.0 percent with the implantation of a bare-metal stent to 4.7 percent with the implantation of a paclitaxel-eluting stent (relative risk, 0.39; 95 percent confidence interval, 0.26 to 0.59; P<0.001). Target-lesion revascularization was required in 3.0 percent of the group that received a paclitaxel-eluting stent, as compared with 11.3 percent of the group that received a bare-metal stent (relative risk, 0.27; 95 percent confidence interval, 0.16 to 0.43; P<0.001). The rate of angiographic restenosis was reduced from 26.6 percent to 7.9 percent with the paclitaxel-eluting stent (relative risk, 0.30; 95 percent confidence interval, 0.19 to 0.46; P<0.001). The nine-month composite rates of death from cardiac causes or myocardial infarction (4.7 percent and 4.3 percent, respectively) and stent thrombosis (0.6 percent and 0.8 percent, respectively) were similar in the group that received a paclitaxel-eluting stent and the group that received a bare-metal stent.

CONCLUSIONS: As compared with bare-metal stents, the slow-release, polymer-based, paclitaxel-eluting stent is safe and markedly reduces the rates of clinical and angiographic restenosis at nine months.

BACKGROUND: Recent studies have suggested that smokers may require less frequent repeated revascularization after percutaneous coronary intervention (PCI) compared with nonsmokers. However, the mechanism of this phenomenon is unknown.

METHODS AND RESULTS: We examined the association between smoking and restenosis using pooled data from 8671 patients treated with PCI in 9 multicenter clinical trials. Clinical restenosis was examined in the cohort of 5682 patients who were assigned to clinical follow-up only. Angiographic restenosis was evaluated in the subset of 2989 patients who were assigned to mandatory angiographic restudy. Among those patients assigned to clinical follow-up only, target lesion revascularization (TLR) occurred in 6.6% of smokers and 10.1% of nonsmokers (P<0.001). After adjustment for baseline clinical and angiographic differences, the rate of TLR remained significantly lower in smokers with an adjusted relative risk of 0.69 (95% CI, 0.54 to 0.88). Among the angiographic cohort, there were no differences in the rates of angiographic restenosis or follow-up diameter stenosis in either univariate or multivariate analyses. This dissociation between clinical and angiographic restenosis was explained in part by reduced sensitivity to restenosis on the part of smokers and by the greater reluctance of smokers to seek medical attention despite recurrent angina.

CONCLUSIONS: In patients undergoing contemporary PCI, cigarette smoking is associated with a lower rate of subsequent TLR without affecting angiographic restenosis. These findings have important implications for the follow-up of smokers after PCI and suggest that cross-study comparisons of rates of clinical restenosis must account for the potential confounding effect of smoking.

  • AU Violaris AG, Thury A, Regar E, Melkert R, Serruys PW
  • SO Heart. 2000;84(3):299.

OBJECTIVES: To assess the influence of smoking on restenosis after coronary angioplasty.

DESIGN AND PATIENTS: The incidence of smoking on restenosis was investigated in 2948 patients. They were prospectively enrolled in four major restenosis trials in which quantitative angiography was used before and immediately after successful angioplasty and again at six months.

RESULTS: Within the study population there were 530 current smokers, 1690 ex-smokers, and 728 non-smokers. Smokers were more likely to be men (85.9% v 87. 5% v 65.3%, current v ex- v non-, p<0.001), to be younger (54.0 (9. 0) v 57.0 (9.1) v 59.9 (9.4) years, p<0.001), to have peripheral vascular disease (7.2% v 5.5% v 2.3%, p<0.001), and have sustained a previous myocardial infarction (42.9% v 43.9% v 37.9%, p = 0.022), but were less likely to be diabetic (9.1% v 9.5% v 12.6%, p = 0.043) or hypertensive (24.9% v 29.3% v 37.2, p50% diameter stenosis) at six months (35.28% v 35.33% v 37.09%, current v ex- v non-), or the absolute loss (0.29 (0.54) v 0.33 (0.52) v 0. 35(0.55) mm, respectively; p = 0.172).

CONCLUSIONS: Although smokers have a lower incidence of known predisposing risk factors for atherosclerosis, they require coronary intervention almost six years earlier than non-smokers and three years earlier than ex-smokers. Once they undergo successful coronary angioplasty, there appears to be no evidence that smoking influences their short term (six month) outcome, but because of the known long term effects of smoking, patients should still be encouraged to discontinue the habit.

  • AU Pache J, Kastrati A, Mehilli J, Schühlen H, Dotzer F, Hausleiter J, Fleckenstein M, Neumann FJ, Sattelberger U, Schmitt C, Müller M, Dirschinger J, Schömig A
  • SO J Am Coll Cardiol. 2003;41(8):1283.

OBJECTIVES: We tested the hypothesis that thinner-strut stents are associated with a reduced rate of restenosis when comparing two stents with different design.

BACKGROUND: We have previously shown that, for two stents with similar design, the risk for restenosis is dependent on the strut thickness. It is unknown whether strut thickness preserves its relevance as a determinant of restenosis even in the presence of different stent designs.

METHODS: A total of 611 patients with symptomatic coronary artery disease were randomly assigned to receive either the thin-strut ACS RX Multilink stent (Guidant, Advanced Cardiovascular Systems, Santa Clara, California) (strut thickness 50 microm, interconnected ring design; n = 309) or the thick-strut BX Velocity stent (Cordis Corp., Miami, Florida) (strut thickness 140 microm, closed cell design; n = 302). The primary end point was angiographic restenosis (>or =50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of target-vessel revascularization (TVR) and the combined rate of death and myocardial infarction (MI) at one year.

RESULTS: The incidence of angiographic restenosis was 17.9% in the thin-strut group and 31.4% in the thick-strut group, relative risk, 0.57 (95% confidence interval, 0.39 to 0.84), p<0.001. A TVR due to restenosis was required in 12.3% of the thin-strut group and 21.9% of the thick-strut group, relative risk, 0.56 (95% confidence interval, 0.38 to 0.84), p = 0.002. No significant difference was observed in the combined incidence of death and MI at one year.

CONCLUSIONS: When two stents with different design are compared, the stent with thinner struts elicits less angiographic and clinical restenosis than the thicker-strut stent.

  • AU Yoshitomi Y, Kojima S, Yano M, Sugi T, Matsumoto Y, Saotome M, Tanaka K, Endo M, Kuramochi M
  • SO Am Heart J. 2001;142(3):445.

BACKGROUND: Experimental studies have revealed that stent configuration influences intimal hyperplasia. The purpose of this study was to evaluate clinical outcomes for 2 stent designs in a randomized trial with quantitative coronary angiography (QCA) and intravascular ultrasonography (IVUS).

METHODS: We randomly assigned 100 patients with 107 lesions and symptomatic coronary artery disease to deployment of a Multilink stent (Advanced Cardiovascular Systems, Guidant, Santa Clara, Calif) or a GFX stent (Applied Vascular Engineering, Santa Rosa, Calif) with IVUS guidance. QCA and IVUS studies were performed before and after intervention and at follow-up (4.2 +/- 1.0 months).

RESULTS: There were no significant differences in baseline characteristics and QCA and IVUS parameters before and after intervention between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger in the Multilink group (2.46 +/- 0.59 vs 2.08 +/- 0.79 mm, P<.05). Maximal in-stent intimal hyperplasia was significantly larger in the GFX group (2.9 +/- 1.7 vs 1.8 +/- 1.2 mm(2), P<.01). The restenosis rate differed between the 2 groups (Multilink 4% vs GFX 26%, P =.003). In multiple stepwise logistic regression analysis, the only predictor that significantly correlated with restenosis was stent type (P<.01). The odds ratio for the GFX stent-treated vessels was 18.65 (95% confidence interval 2.10-165.45).

CONCLUSIONS: With deployment of the GFX stent, a thicker neointima develops within the stent. Stent configuration may affect clinical outcomes.

  • AU Castagna MT, Mintz GS, Leiboff BO, Ahmed JM, Mehran R, Satler LF, Kent KM, Pichard AD, Weissman NJ
  • SO Am Heart J. 2001;142(6):970.

OBJECTIVES: Serial intravascular ultrasonographic (IVUS) studies have shown that in-stent restenosis is the result of intimal hyperplasia (IH). However, routine preintervention IVUS imaging has suggested that many restenotic stents were inadequately deployed. The purpose of this IVUS study was to determine the incidence of mechanical problems contributing to in-stent restenosis (ISR).

METHODS: Between April 1994 and June 2000, 1090 patients with ISR were treated at the Washington Hospital Center. All underwent preintervention IVUS imaging. IVUS measurements included proximal and distal reference lumen areas and diameters; stent, minimum lumen, and IH (stent minus lumen) areas; and IH burden (IH/stent area).

RESULTS: In 49 ISR lesions (4.5%), there were morphologic findings that contributed to the restenosis. These were termed mechanical complications. Examples include (1) missing the lesion (eg, an aorto-ostial stenosis), (2) stent “crush,” and (3) havingthe stent stripped off the balloon during the implantation procedure. Excluding mechanical complications, stent underexpansion was common. In 20% of the ISR cases the stents had a cross-sectional area (CSA) at the site of the lesion<80% of the average reference lumen area. Twenty percent of lesions had a minimum stent area<5.0 mm(2) and an additional 18% had a minimum stent area of 5.0 to 6.0 mm(2). Twenty-four percent of lesions had an IH burden<60%.

CONCLUSION: Mechanical problems related to stent deployment procedures contribute to a significant minority of ISR lesions (approximately 25%).

  • AU Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM
  • SO Circulation. 1990;82(4):1193.

To assess the likelihood of procedural success in patients with multivessel coronary disease undergoing percutaneous coronary angioplasty, 350 consecutive patients (1,100 stenoses) from four clinical sites were evaluated. Eighteen variables characterizing the severity and morphology of each stenosis and 18 patient-related variables were assessed at a core angiographic laboratory and at the clinical sites. Most patients had Canadian Cardiovascular Society class III or IV angina (72%) and two-vessel coronary disease (78%). Left ventricular function was generally well preserved (mean ejection fraction, 58 +/- 12%; range, 18-85%) and 1.9 +/- 1.0 stenoses per patient had attempted percutaneous coronary angioplasty. Procedural success (less than or equal to 50% final diameter stenosis in one or more stenoses and no major ischemic complications) was achieved in 290 patients (82.8%), and an additional nine patients (2.6%) had a reduction in diameter stenosis by 20% or more with a final diameter stenosis 51-60% and were without major complications. Major ischemic complications (death, myocardial infarction, or emergency bypass surgery) occurred in 30 patients (8.6%). In-hospital mortality was 1.1%. Stepwise regression analysis determined that a modified American College of Cardiology/American Heart Association Task Force (ACC/AHA) classification of the primary target stenosis (with type B prospectively divided into type B1 [one type B characteristic]and type B2 [greater than or equal to two type B characteristics]) and the presence of diabetes mellitus were the only variables independently predictive of procedural outcome (target stenosis modified ACC/AHA score; p less than 0.001 for both success and complications; diabetes mellitus: p = 0.003 for success and p = 0.016 for complications). Analysis of success and complications on a per stenosis dilated basis showed, for type A stenoses, a 92% success and a 2% complication rate; for type B1 stenoses, an 84% success and a 4% complication rate; for type B2 stenoses, a 76% success and a 10% complication rate; and for type C stenoses, a 61% success and a 21% complication rate. The subdivision into types B1 and B2 provided significantly more information in this clinically important intermediate risk group than did the standard ACC/AHA scheme. The stenosis characteristics of chronic total occlusion, high grade (80-99% diameter) stenosis, stenosis bend of more than 60 degrees, and excessive tortuosity were particularly predictive of adverse procedural outcome. This improved scheme may improve clinical decision making and provide a framework on which to base meaningful subgroup analysis in randomized trials assessing the efficacy of percutaneous coronary angioplasty.

  • AU Kastrati A, Schömig A, Elezi S, Dirschinger J, Mehilli J, Schühlen H, Blasini R, Neumann FJ
  • SO Circulation. 1999;100(12):1285.

Background-The modified American College of Cardiology/American Heart Association (ACC/AHA) lesion morphology criteria are predictive of early outcome after various coronary catheter interventions. Their potential prognostic value after stent implantation and, in particular, for restenosis and long-term clinical outcome has not been studied. We assessed the prognostic value of the modified ACC/AHA criteria for the long-term angiographic and clinical outcome of patients after coronary stenting. Methods and Results-This study includes 2944 consecutive patients with symptomatic coronary artery disease treated with coronary stent placement. Modified ACC/AHA lesion morphology criteria were used to qualitatively assess the angiograms; type A and B1 lesions were categorized as simple, and type B2 and C lesions were designated complex. Primary end points were angiographic restenosis and 1-year event-free survival. Restenosis rate was 33.2% in complex lesions and 24.9% in simple lesions (P<0.001). It was 21. 7% for type A, 26.3% for type B1, 33.7% for type B2, and 32.6% for type C lesions. One-year event-free survival was 75.6% for patients with complex lesions and 81.1% for patients with simplelesions (P50% by QCA. IVUS predictors were minimum and mean in-stent area, stent length, and in-stent diameter. Multiple models were constructed with multivariate logistic regression analysis. The model containing minimum in-stent area and stent length best fit the Hosmer-Lemeshow goodness-of-fit test. This model was used to construct a reference chart to calculate the expected 6-month restenosis rate.

CONCLUSIONS: The expected 6-month in-stent restenosis rate after stent implantation for short lesions in relatively large vessels can be predicted by use of in-stent minimal area (which is inversely related to restenosis) and stent length (which is directly related to restenosis), both of which can be read from a simple reference chart.

  • AU Kastrati A, Schömig A, Elezi S, Schühlen H, Wilhelm M, Dirschinger J
  • SO Circulation. 1998;97(24):2396.

BACKGROUND: Little is known about the behavior with regard to restenosis of multiple lesions within the same patient treated with intracoronary stenting. Our objective was to test the hypothesis that there is an intrapatient dependence of restenosis between lesions.

METHODS AND RESULTS: Quantitative analysis was carried out on angiograms obtained before, immediately after, and at 6 months after coronary stent placement in 1734 lesions in 1244 patients. We used a specialized logistic regression that not only accounts for intraclass correlation but also quantifies it in the form of odds ratio (OR) as the change in risk of a lesion to develop restenosis if another companion lesion had restenosis. The model was based on 23 patient- and lesion-related variables with binary restenosis (diameter stenosis>or =50%) as end point. The overall restenosis rate was 27.5%: 24.4% for single-lesion, 28.6% for double-lesion, and 33.8% for>or =3-lesion interventions. After adjustment for the influence of significant factors (hypercholesterolemia, systemic arterial hypertension, diabetes mellitus, previous PTCA, ostial lesion, location in left anterior descending coronary artery, number of stents placed, vessel size, stenosis severity, balloon-to-vessel ratio, and final result), the analysis found a significant intrapatient correlation, OR 2.5 (1.8 to 3.6). This means that in patients with multilesion interventions, the risk of a lesion to develop restenosis is 2.5 times higher if a companion lesion has restenosis, independently of the presence or absence of analyzed patient risk factors (eg, diabetes).

CONCLUSIONS: This study demonstrates that there is a dependence of restenosis between coronary lesions in patients who undergo a multilesion intervention. The likelihood of restenosis for a lesion is higher when another companion lesion has also developed restenosis. Other, as yet unidentified patient factors may be the source of this intrapatient correlation of restenosis.

  • AU Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB
  • SO J Am Coll Cardiol. 2002;39(7):1113.

OBJECTIVES: We sought to determine the effect of varying degrees of renal insufficiency on death and cardiac events during and after a percutaneous coronary intervention (PCI).

BACKGROUND: Patients with end-stage renal disease have a high mortality from coronary artery disease. Little is known about the impact of mild and moderate renal insufficiency on clinical outcomes after PCI.

METHODS: Cardiac mortality and all-cause mortality were determined for 5,327 patients undergoing PCI from January 1, 1994, to August 31, 1999, at the Mayo Clinic, based on the estimated creatinine clearance or whether the patient was on dialysis.

RESULTS: In-hospital mortality was significantly associated with renal insufficiency (p = 0.001). Even after successful PCI, one-year mortality was 1.5% when the creatinine clearance was>or =70 ml/min (n = 2,558), 3.6% when it was 50 to 69 ml/min (n = 1,458), 7.8% when it was 30 to 49ml/min (n = 828) and 18.3% when it was<30 ml/min (n = 141). The 18.3% mortality rate for the group with<30 ml/min creatinine clearance was similar to the 19.9% mortality rate in patients on dialysis (n = 46). The mortality risk was largely independent of all other factors.

CONCLUSIONS: Renal insufficiency is a strong predictor of death and subsequent cardiac events in a dose-dependent fashion during and after PCI. Patients with renal insufficiency have more baseline cardiovascular risk factors, but renal insufficiency is associated with an increased risk of death and other adverse cardiovascular events, independent of all other measured variables.

Recent studies have shown that patients with mild chronic renal insufficiency (CRI) have a high prevalence of cardiovascular disease and cardiac death. Furthermore, patients with CRI undergoing percutaneous coronary intervention have a higher rate of in-hospital and long-term morbidity and mortality. A recent retrospective subgroup analysis of  patients with CRI undergoing percutaneous intervention suggests that the use of stents may improve their in-hospital and long-term outcomes.

OBJECTIVE: To investigate 4-year outcomes and predictors of repeat revascularization in patients treated with Resolute™zotarolimus-eluting stent (R-ZES) and XIENCE V™everolimus-eluting stent (EES) in the RESOLUTE All Comers trial.

BACKGROUND: Data on long-term outcomes of new generation drug-eluting stents are limited, and predictors of repeat revascularization due to restenosis and/or progression of disease are largely unknown.

METHODS: Patients were randomly assigned to treatment with R-ZES (n=1,140) or EES (n=1,152). We assessed pre-specified safety and efficacy outcomes at 4 years including target-lesion failure (TLF) and stent thrombosis (ST). Predictors of revascularization at 4 years were identified by Cox regression analysis.

RESULTS: At 4 years, rates of TLF (15.2% vs. 14.6%, p=0.68), cardiac death (5.4% vs. 4.7%, p=0.44), target-vessel myocardial infarction (MI) (5.3% vs. 5.4%, p=1.00), clinically-indicated target-lesion revascularization (TLR) (7.0% vs. 6.5%, p=0.62), and definite/probable ST (2.3% vs. 1.6%, p=0.23) were similar with R-ZES and EES. Independent predictors of TLR were: age, insulin-treated diabetes, SYNTAX score, treatment of saphenous vein grafts, ostial lesions, and instent restenosis. Independent predictors of any revascularization were: age, diabetes, previous PCI, ST-elevation MI, smaller reference vessel diameter, SYNTAX score, and treatment of left anterior descending, right coronary artery, saphenous vein grafts, ostial lesions, or instent restenosis.

CONCLUSIONS: R-ZES and EES demonstrated similar safety and efficacy throughout 4 years. TLR represented less than half of all repeat revascularization procedures. Patient and lesion-related factors predicting the risk of TLR and any revascularization showed considerable overlap.

CLINICAL TRIAL INFO: RESOLUTE All Comers; NCT00617084.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) has been thought to present in a stable manner as exertional angina. However, the presentation of in-stent restenosis (ISR) is not well-studied. We hypothesized that a substantial proportion of bare metal ISR presents as acute coronary syndromes. We aimed to characterize the severity of the clinical presentation of ISR.

METHODS: We searched our PCI database for all cases of PCI for bare metal ISR occurring between May 1999 and September 2003. Multivessel interventions were excluded. In-stent restenosis presentation was classified into three categories: (1) myocardial infarction (MI), (2) unstable angina requiring hospitalization before angiography, and (3) exertional angina. Routine angiographic screening after initial stent placement was not performed, so ISR episodes were clinical, rather than angiographic, ISR.

RESULTS: We identified 1186 cases of bare metal ISR in 984 patients. Median age was 63, 72% were male, and 36% had diabetes. Of the ISR episodes, 9.5% presented as acute MI (7.3% as non-ST-segment elevation MI and 2.2% as ST-segment elevation MI), 26.4% as unstable angina requiring hospitalization before angiography, and 64.1% as exertional angina.

CONCLUSIONS: More than one third of bare metal ISR episodes presented as MI or unstable angina requiring hospitalization. The acuity of the clinical presentation of bare metal ISR appears to be more severe than has been previously thought. Aggressive efforts, such as drug-eluting stents to decrease the incidence of unstable angina due to bare metal ISR, are warranted.

 

OBJECTIVES: We sought to evaluate the long-term clinical outcome of patients undergoing successful balloon angioplasty for in-stent restenosis, and to determine correlates of the need for subsequent target lesion revascularization (TLR).

BACKGROUND: In-stent restenosis can be safely treated by repeat percutaneous intervention. Reported subsequent TLR rates have varied from 20% to 80% and seem related to the type of restenotic lesion.

METHODS: The study population comprised 234 patients with follow-up data who were successfully treated with repeat balloon angioplasty for in-stent restenosis in 257 lesions between May 1995 and January 1998 at our institution.

RESULTS: Clinical follow-up was available at 459 (286 to 693) days after the repeat procedure. Event-free survival was 78.5% and 74.6% at 12 and 24 months, respectively. Recurrent events occurred in 58patients (24.8%), including 6 deaths (2.6%), 4 myocardial infarction (1.7%) and repeat target vessel revascularization in 50 patients (21.4%). Independent predictors of repeat TLR were time to in-stent restenosis<90 days (Hazard ratio 4.67, p<0.001), minimal luminal diameter after repeat procedure (Hazard ratio 0.38, p = 0.034) and the angiographic pattern of in-stent restenosis (Hazard ratio 1.65, p = 0.036).

CONCLUSIONS: Balloon angioplasty is an effective means of treating in-stent restenosis. The long-term results are acceptable particularly for focal restenotic lesions. Further restenosis is more common in patients with early initial recurrence, more proliferative lesions and a poorer angiographic result from repeat angioplasty.

 

Coronary stents have been the major advancement in percutaneous coronary intervention in the last decade and are used in 60% to 80% of patients. However, in-stent restenosis continues to be a problem, occurring in 20% to 30% of cases. The clinical presentation of patients who develop restenosis after stenting has not been well characterized. In this study we compared the clinical presentation of in-stent restenosis with that of restenosis without stenting. Of 739 patients who underwent percutaneous coronary intervention and had repeat catheterization between October 1, 1997, and June 30, 2000, 262 consecutive patients with recurrent ischemia and restenosis were identified: 191 patients with (group A) and 71 without (Group B) stenting. Patients who underwent interventions in bypass grafts and those who developed early acute stent thrombosis were excluded from the study. Recurrent clinical ischemia occurred at a mean of 5.5 months in group A and 6.5 months in group B (p = 0.24). Rest angina (Braunwald class II and III) was more frequent in group A (48% vs 32%, p = 0.032). Acute coronary syndromes, the combination of rest angina, and acute myocardial infarction were also more frequent in group A (68% vs 46%, p = 0.03). Patients in group A were more likely to have angiographically visible thrombus than those in group B (9% vs 0%, p = 0.02). Thus, acute coronary syndromes are a common clinical presentation of restenosis among patients whose follow-up angiogram is obtained for clinical reasons, and occur more frequently in patients with in-stent restenosis than in those with restenosis without stenting.

 

OBJECTIVES: The purpose of this study was to examine the outcomes of patients who developed coronary in-stent restenosis (ISR) or stent thrombosis (STH) inside drug-eluting stents (DES).

BACKGROUND: Drug-eluting stents have markedly reduced the incidence of restenosis. However, when restenosis occurs within a DES, its optimal management remains unclear.

METHODS: We retrospectively analyzed clinical and angiographic data from 92 patients who underwent revascularization for ISR (n = 84) or STH (n = 8) within a DES at our institution. Regular follow-ups were available up to 2 years. We recorded the occurrence of major adverse cardiac events (MACE), defined as deaths from all causes, myocardial infarction (MI), or target lesion revascularization (TLR), among patients treated by the “DES sandwich” technique or by other treatment methods.

RESULTS: In-hospital MACE included 1 periprocedural MI and 2 deaths. Over a mean follow-up of 15 +/- 6 months, the overall rates of death, MI, and TLR were 8.7%, 2.2%, and 30.6%, respectively. By actuarial analysis, the 12-month TLR and MACE rates were 28.2% and 42.9%, respectively.

CONCLUSIONS: Current treatments of ISR or STH in DES are associated with a high long-term rate of MACE.

 

BACKGROUND: Limited information is available regarding restenosis after implantation of a sirolimus-eluting stent (SES).

OBJECTIVE: To report on angiographic characteristics, clinical presentation and treatment of this particularly complex type of coronary lesion.

METHODS AND RESULTS: A total of 1424 SES were implanted in 1159 patients (average 1.2 per patient) for chronic or acute coronary syndromes in the University Hospital of Siena (Siena, Italy), which is a tertiary centre. Symptomatic in-SES restenosis was observed in 26 patients (2.2%) at 10+/-5 months (median eight months, range four to 23 months) following the initial intervention. In-SES restenosis was associated with stable angina in 16 patients, acute myocardial infarction in three patients and unstable angina in seven patients. Two patients had restenosis in two separate SES. Conditions often associated with in-SES restenosis included treatment of chronic total occlusion, geographic miss or in-stent restenosis during the index procedure. Among the first 20 patients, those with focal, in-body SES (type Ic) restenosisreceived balloon-only angioplasty, and patients with other patterns received repeat SES implantation. Clinical and angiographic follow-up (average 16+/-7 months) recorded one death (noncardiac) in the balloon-only group and four cases of unstable angina (three due to relapsing in-SES restenosis in the balloon-only group and the fourth due to a de novo lesion). Follow-up quantitative angiography showed a higher incidence of binary restenosis after balloon-only treatment (57% versus 17%; P<0.05), as well as higher lumen loss and loss index (Por =10 mm) inside the stent (71%) or focal (29%). Mean stent length was 16+/-7 mm. Balloon diameter of2.98+/-0.37 mm and maximal inflation pressure of 10+/-3 atm were used for balloon angioplasty. Angiographic success rate was 100% without any complication. Acute gain was lower after balloon angioplasty for in-stent restenosis than after stent implantation: 1.19+/-0.60 mm vs. 1.75+/-0.68 mm (p=0.0002). At 6-month follow-up, 60% of patients were asymptomatic and no patient died. Eighteen patients (35%) had repeat target vessel revascularization. Angiographic restenosis rate was 54%. Recurrent restenosis rate was higher when in-stent restenosis was diffuse: 63% vs. 31% when focal, p=0.046.

CONCLUSIONS: Although balloon angioplasty for in-stent restenosis can be safely and successfully performed, it leads to less immediate stenosis improvement than at time of stent implantation and carries a high recurrent angiographic restenosis rate at 6 months, in particular in diffuse in-stent restenosis lesions.

 

BACKGROUND: In-stent restenosis is an increasing clinical problem. Discordant results have been published regarding the risk of recurrent restenosis after repeat angioplasty for the treatment of in-stent restenosis.

METHODS AND RESULTS: One hundred three consecutive patients (107 vessels) underwent repeat percutaneous intervention for the treatment of in-stent restenosis and were entered in a prospective angiographic follow-up program. Repeat balloon angioplasty was performed at 93 lesions (87%) and additional stenting at 14 lesions (13%). The primary success rate was 98%. Six-month angiographic follow-up was performed in 85% of eligible patients. Restenosis was determined by quantitative angiography. Restenosis defined as a>50% diameter stenosis at follow-up was observed at 22% of lesions. The rate of target-lesion revascularization at 6 months was 17%. Repeat intervention for diffuse in-stent restenosis and severe stenosis before repeat intervention were associated with significantly higher rates of recurrent restenosis.

CONCLUSIONS: The overall restenosis rate after repeat intervention for in-stent restenosis is low. Thesubgroup of patients with diffuse and/or severe in-stent restenosis, however, is at higher risk of recurrent restenosis and may benefit from alternative therapeutic strategies.

 

OBJECTIVES: This randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR).

BACKGROUND: Stent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high.

METHODS: We randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events.

RESULTS: Procedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 +/- 0.4 vs. 2.25 +/- 0.5 mm, por =3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting.

CONCLUSIONS: In patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome.

 

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 to5 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.

 

BACKGROUND: Although both percutaneous transluminal coronary angioplasty (PTCA) and additional stenting can be used for the treatment for focal in-stent restenosis (ISR), no large-scale comparative data on the clinical outcomes after these interventional procedures have been reported.

METHODS: In the current study we compared the in-hospital and long-term clinical results of PTCA alone (n = 266 patients, n = 364 lesions) versus stenting (n = 135 patients, n = 161 lesions) for the treatment of focal ISR, defined as a lesion length less than or equal to 10 mm.

RESULTS: There were significantly more diabetic patients in the PTCA group than in the stent group (36% vs 26%, P =.04), but other baseline characteristics were similar. Lesion length and preprocedure minimal lumen diameter (MLD) were also similar in the two groups, but the stent group had a larger reference vessel diameter (3.40 +/- 0.73 mm vs 2.99 +/- 0.68 mm, P<.001). Stenting achieved a larger postprocedure MLD than PTCA did (2.95 +/- 0.95 mm vs 2.23 +/- 0.60 mm, P5 times normal was more frequent with stent (18.5% vs 9.7%, P =.05). At 1 year the two interventional strategies had similar cumulative mortality (4.6% PTCA vs 5.1% stent, P not significant) and target lesion revascularization rate (24.6% PTCA vs 26.5% stent, P not significant). By multivariate analysis, the sole predictor of target lesion revascularization was diabetes (odds ratio 2.4, 95% confidence intervals 1.2-4.7, P =.01).

CONCLUSION: Repeat stenting for the treatment of focal ISR had a higher postprocedure creatine kinase myocardial band elevation rate and similar long-term clinical results compared with PTCA alone.

 

BACKGROUND: We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis.

METHODS AND RESULTS: Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07+/-0.2 mm in-stent and -0.05+/-0.3 mm in-lesion at 4 months, and 0.36+/-0.46 mm in-stent and 0.16+/-0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92+/-1.9 mm(3) at 4 months and 2.55+/-4.9 mm(3) after 1 year. Percent volume obstruction was 0.81+/-1.7% and 1.76+/-3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations.

CONCLUSION: This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.

 

OBJECTIVES: In this study, we assess the value of sirolimus eluting stent (SES) implantation in patients with complex in-stent restenosis (ISR).

BACKGROUND: The treatment of ISR remains a therapeutic challenge, since many pharmacological and mechanical approaches have shown disappointing results. The SESs have been reported to be effective in de-novo coronary lesions.

METHODS: Sixteen patients with severe, recurrent ISR in a native coronary artery (average lesion length 18.4 mm) and objective evidence of ischemia were included. They received one or more 18 mm Bx VELOCITY SESs (Cordis Waterloo, Belgium). Quantitative angiographic and three-dimensional intravascular ultrasound (IVUS) follow-up was performed at four months, and clinical follow-up at nine months.

RESULTS: The SES implantation (n = 26) was successful in all 16 patients. Four patients had recurrent restenosis following brachytherapy, and three patients had totally occluded vessels preprocedure. At four months follow-up, one patient had died and three patients had angiographic evidence of restenosis (one in-stent and two in-lesion). In-stent late lumen loss averaged 0.21 mm and the volume obstruction of the stent by IVUS was 1.1%. At nine months clinical follow-up, three patients had experienced four major adverse cardiac events (two deaths and one acute myocardial infarction necessitating repeat target vessel angioplasty).

CONCLUSIONS: The SES implantation in patients with severe ISR lesions effectively prevents neointima formation and recurrent restenosis at four months angiographic follow-up.

 

BACKGROUND: The first clinical study of paclitaxel-eluting stent for de novo lesions showed promising results. We performed the TAXUS III trial to evaluate the feasibility and safety of paclitaxel-eluting stent for the treatment of in-stent restenosis (ISR).

METHODS AND RESULTS: The TAXUS III trial was a single-arm, 2-center study that enrolled 28 patients with ISR meeting the criteria of lesion lengthor =50%) at 6-month follow-up angiography based on “in-segment” analysis. Primary analysis was comparison between stent groups and balloon angioplasty groups; a secondary analysis compared sirolimus and paclitaxel stents.

RESULTS: Follow-up angiography was performed in 275 (92%) of 300 patients. The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.

CONCLUSIONS: In patients with in-stent restenosis, a strategy based on sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.

 

OBJECTIVES: We sought to assess the effectiveness of sirolimus-eluting stents (SES) in patients with in-stent restenosis (ISR).

BACKGROUND: Treatment of patients with ISR remains a challenge.

METHODS: The Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) study is a multicenter randomized trial conducted in 150 patients with ISR (76 allocated to SES and 74 to balloon angioplasty [BA]). The primary end point was recurrent restenosis rate at nine months. Secondary end points included prespecified subgroup analysis, lumen volume on intravascular ultrasound (IVUS), and a composite of major clinical events at one year.

RESULTS: Angiographic success was obtained in all patients. At 9-month angiographic follow-up (96% of eligible patients) minimal lumen diameter was larger (2.52 mm [interquartile range (IQR) 2.09 to 2.81]vs. 1.54 mm [IQR 0.91 to 2.05]; p<0.001) and recurrent restenosis rate was lower (11% vs. 39%; p<0.001) in the SES group. Prespecified subgroup analyses were consistent with the main outcome measure. Lumen volume on IVUS at 9 months was also larger (279 mm3 [IQR 227 to 300]vs. 197 mm3 [IQR 177 to 230]; p<0.001) in the SES group. At one-year clinical follow-up (100% of patients), the event-free survival (freedom from death, myocardial infarction, and target vessel revascularization) was significantly improved in the SES group (88% vs. 69%; p<0.004) as the result of a lower requirement for target vessel revascularization (11% vs. 30%; p<0.003).

CONCLUSIONS: In patients with ISR, the use of SES provides superior long-term clinical, angiographic, and IVUS outcome than BA treatment.

 

Few data are available on the effectiveness of sirolimus-eluting stent implantation for the treatment of in-stent restenosis, and no data exist about the predictors of outcome after sirolimus-eluting stent implantation for complex in-stent restenosis (diffuse, proliferative, or total occlusion). From April 2002 to May 2004, 136 patients with 161 complex in-stent restenoses underwent sirolimus-eluting stent implantation. At 9 months, 5 patients had died (3 of cardiac and 2 of noncardiac causes), no reinfarctions had occurred, and 11 target vessel revascularization procedures had been performed. The target vessel revascularization rate was 8%, and the in-segment binary restenosis rate was 17%. The predictors of the risk of recurrence were unstable angina as the clinical presentation of in-stent restenosis, an ostial location of the target lesion, lesion length, and sirolimus-eluting stent diameter<or =2.5 mm.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical outcome of the efficacy and safety of sirolimus-eluting stents (SES) for in-stent restenosis (ISR) in the TRUE (Tuscany Registry of Unselected In-Stent Restenosis) database.

BACKGROUND: The TRUE registry demonstrated that SES in the treatment of bare-metal stent ISR is efficacious (5% of target lesion revascularization [TLR]) and safe (stent thrombosis<1%) at 9 months. Clinical outcome at 4 years is reported.

METHODS: A total of 244 patients with ISR who were treated with SES implantation represent the study population. The incidence of major adverse cardiac events was collected at 4 years.

RESULTS: At 4-year follow-up, overall mortality was 9.8% (24 patients). Cardiac death occurred in 11 (4.5%), nonfatal myocardial infarction in 8 (3.2%), and TLR in 27 (11.1%) patients for a cumulative event-free survival rate of 80.3%. Definite stent thrombosis occurred in 5 (2%) patients and possible stent thrombosis in 2 (0.8%). Diabetes remained an independent negative predictor of freedom from TLR (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.20 to 0.71, p = 0.002) and major adverse cardiac events (OR: 0.38; 95% CI: 0.20 to 0.71, p = 0.002).

CONCLUSIONS: The clinical benefit of SES implantation for bare-metal stent ISR is maintained at 4 years with a low TLR rate and an overall incidence of stent thrombosis of 0.7% per year.

 

In patients with stable CAD, PCI can be considered a valuable initial mode of revascularization in all patients with objective large ischaemia in the presence of almost every lesion subset, with only one exception: chronic total occlusions that cannot be crossed. In early studies, there was a small survival advantage with CABG surgery compared with PCI without stenting. The addition of stents and newer adjunctive medications improved the outcome for PCI. The decision to recommend PCI or CABG surgery will be guided by technical improvements in cardiology or surgery, local expertise, and patients’ preference. However, until proved otherwise, PCI should be used only with reservation in diabetics with multi-vessel disease and in patients with unprotected left main stenosis. The use of drug-eluting stents might change this situation. Patients presenting with NSTE-ACS (UA or NSTEMI) have to be stratified first for their risk of acute thrombotic complications. A clear benefit from early angiography (<48 h) and, when needed, PCI or CABG surgery has been reported only in the high-risk groups. Deferral of intervention does not improve outcome. Routine stenting is recommended on the basis of the predictability of the result and its immediate safety. In patients with STEMI, primary PCI should be the treatment of choice in patients presenting in a hospital with PCI facility and an experienced team. Patients with contra-indications to thrombolysis should be immediately transferred for primary PCI, because this might be their only chance for quickly opening the coronary artery. In cardiogenic shock, emergency PCI for complete revascularization may be life-saving and should be considered at an early stage. Compared with thrombolysis, randomized trials that transferred the patients for primary PCI to a ‘heart attack centre’ observed a better clinical outcome, despite transport times leading to a significantly longer delay between randomization and start of the treatment. The superiority of primary PCI over thrombolysis seems to be especially clinically relevant for the time interval between 3 and 12 h after onset of chest pain or other symptoms on the basis of its superior preservation of myocardium. Furthermore, with increasing time to presentation, major-adverse-cardiac-event rates increase after thrombolysis, but appear to remain relatively stable after primary PCI. Within the first 3 h after onset of chest pain or other symptoms, both reperfusion strategies seem equally effective in reducing infarct size and mortality. Therefore, thrombolysis is still a viable alternative to primary PCI, if it can be delivered within 3 h after onset of chest pain or other symptoms. Primary PCI compared with thrombolysis significantly reduced stroke. Overall, we prefer primary PCI over thrombolysis in the first 3 h of chest pain to prevent stroke, and in patients presenting 3-12 h after the onset of chest pain, to salvage myocardium and also to prevent stroke. At the moment, there is no evidence to recommend facilitated PCI. Rescue PCI is recommended, if thrombolysis failed within 45-60 min after starting the administration. After successful thrombolysis, the use of routine coronary angiography within 24 h and PCI, if applicable, is recommended even in asymptomatic patients without demonstrable ischaemia to improve patients’ outcome. If a PCI centre is not available within 24 h, patients who have received successful thrombolysis with evidence of spontaneous or inducible ischaemia before discharge should be referred to coronary angiography and revascularized accordingly–independent of ‘maximal’ medical therapy.

CONTEXT: Restenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although subsequent recurrence rates are high, with vascular brachytherapy (VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established.

OBJECTIVE: To investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries.

DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5-3.75 mm; lesion length,<or =46 mm).

INTERVENTIONS: Patients were randomly assigned to undergo angioplasty followed by VBT with a beta source (n = 201) or paclitaxel-eluting stent implantation (n = 195). Clinical and angiographic follow-up at 9 months was scheduled in all patients.

MAIN OUTCOME MEASURE: Ischemia-driven target vessel revascularization at 9 months.

RESULTS: Diabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic target lesion revascularization were 27 (13.9%) vs 12 (6.3%) (relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P = .01); for ischemic target vessel revascularization, 34 (17.5%) vs 20 (10.5%) (RR, 0.60; 95% CI, 0.36-1.00; P = .046); and for overall major adverse cardiac events, 39 (20.1%) vs 22 (11.5%) (RR, 0.57; 95% CI, 0.35-0.93; P = .02), with similar rates of cardiac death or myocardial infarction (10 [5.2%]vs 7 [3.7%]; RR, 0.71; 95% CI, 0.28-1.83; P = .48) and target vessel thrombosis (5 [2.6%]vs 3 [1.6%]; RR, 0.61; 95% CI, 0.15-2.50; P = .72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents (RR, 0.47; 95% CI, 0.30-0.71; P<.001).

CONCLUSION: Treatment of bare-metal in-stent restenotic lesions with paclitaxel-eluting stents rather than angioplasty followed by VBT reduces clinical and angiographic restenosis at 9 months and improves event-free survival.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00287573.

 

AIMS: This study sought to investigate the 2-year outcomes of patients treated with the paclitaxel-eluting TAXUS((R)) stent (PES) or vascular brachytherapy (VBT), the previous ‘gold standard therapy’, for bare metal stent in-stent restenosis (ISR).

METHODS AND RESULTS: In the TAXUS V-ISR trial, 396 patients with bare metal stent ISR referred for percutaneous coronary intervention were prospectively randomized to either PES or beta source VBT. The present analysis reports 24-month clinical outcomes from that study. Between 9 and 24 months, ischaemia-driven target lesion revascularization tended to be required less frequently with assignment to PES compared to VBT (5.3 vs. 10.3%, P = .07). As a result, ischaemia-driven target lesion revascularization at 24 months was significantly reduced with PES compared with VBT (10.1 vs. 21.6%, P = 0.003), as was ischaemia-driven target vessel revascularization (18.1 vs. 27.5%, P = .03). There were no significant differences between the two groups with regard to death, myocardial infarction, or target vessel thrombosis either between 12 and 24 months, or cumulative to 24 months.

CONCLUSION: Freedom from clinical restenosis at 2 years is significantly enhanced after PES placement compared with VBT for bare metal stent ISR, with similar rates of death, myocardial infarction, and target vessel thrombosis.

 

CONTEXT: Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited.

OBJECTIVE: To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent.

DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005.

INTERVENTIONS: Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259).

MAIN OUTCOME MEASURE: Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure.

RESULTS: Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55]mm vs 17.22 [7.97]mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63]mm vs 1.80 [0.63]mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60]vs 1.0 [0.61]mm; P<.001) due to stenting and no edge restenosis.

CONCLUSION: Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00231257.

 

The greatest recent mechanical advance in percutaneous coronary revascularization (PCR) has been the development of bare-metal stents, which compared with traditional balloon angioplasty substantially reduce angiographic restenosis and the need for repeat target vessel revascularization (TVR). Stents provide a larger arterial lumen diameter immediately postprocedure (acute gain), although their drawback is an increased reparative response of neointimal formation (late loss). Fortunately, the net gain remains greatest with stents compared with other PCR devices. In less complex lesions, the rate of TVR with bare-metal stents is approximately 10% to 15%, although this rate has been reported to be 2- to 3-fold higher in more complex lesions and unique patient subsets.1,2 In 2003, at a time when the use of bare-metal stents peaked, approximately 1 million coronary stents were placed in patients hospitalized in the United States.3 Even with a conservative estimate, this means at least 100 000 in-stent restenotic lesions occurred, making this an important clinical problem.

BACKGROUND: We evaluated the clinical and angiographic outcomes of patients presenting with restenosis after sirolimus-eluting stent (SES) implantation treated with repeated percutaneous intervention.

METHODS AND RESULTS: A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, 1 (4%) was re-treated with a bare stent, 3 (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated drug-eluting stent implantation (SES in 12 lesions [44%], paclitaxel-eluting stents in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42.9%. The risk of recurrent restenosis was increased for patients with hypercholesterolemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with drug-eluting stents was 18.2%.

CONCLUSIONS: Even though de novo lesions treated with SES at baseline and re-treated with drug-eluting stents had reasonably better outcomes than other lesion types and strategies, our study shows that the treatment of post-SES restenosis is currently suboptimal and warrants further investigation.

 

Although clinical outcomes after sirolimus-eluting stents (SESs) have been previously described (“primary” success rates), the fate of patients whose SES implantation fail and who require ischemia-driven target lesion revascularization is poorly understood. The SIRIUS trial is a prospective, randomized, clinical trial that includes 533 evaluable patients with SESs. Twenty-two of these patients had adjudicated ischemia-driven target lesion revascularization (4.1%) within the first year of follow-up and comprised the study population of this analysis. Of these patients, 11 (50%) had diabetes, and restenotic lesions were focal and located at the proximal stent edge in 91% and 73% of patients, respectively. Restenosis was treated with bare metal stent implantation, balloon dilatation, or intravascular brachytherapy in 82%, 13.5%, and 4.5% of patients, respectively. At 1-year follow-up after the first recurrence (2-year follow-up after the index procedure), only 5 of these patients (23%) required a second repeat revascularization procedure. Risk factors for a second recurrence after treatment of SES restenosis were female gender, long lesions that required long stents at the index procedure, and an early first recurrence. In conclusion, SES failure treated with traditional percutaneous coronary intervention yielded good outcome at 1-year follow-up (secondary failure rate only 23%), perhaps due to the focal nature of the SES restenotic lesion. Future studies should evaluate other methods, including drug-eluting stents, to further optimize the outcome of treatment of SES failures.

 

  • AD Columbia University Medical Center-New York Presbyterian Hospital and Cardiovascular Research Foundation, New York, New York, USA. imoussa@crf.org
  • PMID 16728218
  • TI Drug-eluting stent restenosis: the pattern predicts the outcome.
  • AU Cosgrave J, Melzi G, Biondi-Zoccai GG, Airoldi F, Chieffo A, Sangiorgi GM, Montorfano M, Michev I, Carlino M, Bonizzoni E, Colombo A
  • SO J Am Coll Cardiol. 2006;47(12):2399.

OBJECTIVES: We sought to determine if the angiographic pattern of in-stent restenosis in drug-eluting stents (DES) maintains its prognostic importance.

BACKGROUND: The pattern of restenosis in the bare-metal stent era had a significant impact on therapeutic outcomes.

METHODS: We identified a total of 250 consecutive restenotic lesions in 203 patients (66.4% sirolimus-eluting stents and 33.6% paclitaxel-eluting stents). We divided these lesions into two groups: focal, defined as<or =10 mm, 163 lesions (65.2%); and nonfocal, which were diffuse, proliferative, or obstructive, 87 lesions (34.8%). The end points analyzed were angiographic restenosis and target lesion revascularization (TLR).

RESULTS: Diabetes was the only clinical variable associated with the pattern of restenosis (28.8% focal compared with 52.9% diffuse; p = 0.0001). Angiographic follow-up of the treatment of restenosis was available in 61.2% of the lesions and was similar between the two groups. The rate of angiographic restenosis was 17.8% in the focal group and 51.1% in the nonfocal group (p = 0.0001). The incidence of TLR also increased with the type of restenosis treated (9.8% and 23%, respectively; p = 0.007). An adjusted multivariate analysis revealed that the pattern of restenosis remained associated with both the occurrence of restenosis and TLR (odds ratio [OR]5.1 [95% confidence interval (CI) 1.1 to 23], p = 0.03; and OR 3.61 [95% CI 1.2 to 10.9], p = 0.02; respectively).

CONCLUSIONS: Similar to bare-metal stent data, the angiographic pattern of restenosis following DES implantation is prognostically important. Diabetes is a significant predictor of the pattern of restenosis in the DES era.

 

OBJECTIVE: The authors aimed to compare the clinical outcomes with repeat drug-eluting stent (DES) implantation utilizing the same type versus an alternate DES type for in-stent restenosis (ISR) of DES.
BACKGROUND: : DES are proven as an effective treatment for bare metal ISR.
METHODS: A cohort of 116 patients previously treated with a sirolimus-eluting stent (SES) or a paclitaxel-eluting stent (PES) who presented with angiographic ISR were treated with repeat DES. Of these, 62 (53.4%) were treated with different DES and 54 (46.6%) were treated with the same DES. This cohort was followed for clinical events at 30 days, 6 months, and 1 year.
RESULTS: Baseline characteristics were similar except for more diabetes among patients receiving the different type of DES. Of the 116, overall 16.4% of the DES were implanted for previous ISR and 2.6% had previously received brachytherapy. At 6 months, the overall target vessel revascularization (TVR) rate was 12.2% for the entire cohort. The TVR-major adverse cardiac event (MACE) rate for the patients treated with different DES was 14.5% and 16.7% for the same DES (P = 0.750). Overall TVR rate at 1 year was 28.8%. The TVR-MACE was 32.6% for different DES and 35.0% for the same DES (P = 0.814).
CONCLUSIONS: Reimplantation of DES for the treatment of DES ISR (same or different) is safe but associated with a high rate of recurrences at 1 year regardless of the initial DES type. Other treatment modalities for ISR of DES should be considered to further improve the overall TVR-MACE.

 

BACKGROUND: Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet.
METHODS AND RESULTS: During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P50%) at 6- to 8-month follow-up, target lesion revascularization, the composite of death or myocardial infarction, and definite stent thrombosis at 12 months.
RESULTS: Regarding anti-restenotic efficacy, there were no differences between SES and PES in late loss (0.40 +/- 0.65 mm vs. 0.38 +/- 0.59 mm; p = 0.85), binary restenosis (19.6% vs. 20.6%; p = 0.69), or target lesion revascularization (16.6% vs. 14.6%; p = 0.52). In terms of safety outcomes, the rates of death/myocardial infarction (6.1% vs. 5.8%; p = 0.86) and stent thrombosis (0.4% vs. 0.4%; p>0.99) were also similar.
CONCLUSIONS: In cases of SES restenosis, treatment with either repeat SES or switch to PES was associated with a comparable degree of efficacy and safety. Drug resistance at an individual patient level may play a contributory role to the somewhat higher than expected late loss observed with the SES in the current study. (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2 [ISAR-DESIRE 2]; NCT00598715).

 

BACKGROUND: Treatment of coronary in-stent restenosis is hampered by a high incidence of recurrent in-stent restenosis. We assessed the efficacy and safety of a paclitaxel-coated balloon in this setting.
METHODS: We enrolled 52 patients with in-stent restenosis in a randomized, double-blind, multicenter trial to compare the effects of a balloon catheter coated with paclitaxel (3 microg per square millimeter of balloon surface area) with those of an uncoated balloon catheter in coronary angioplasty. The primary end point was late luminal loss as seen on angiography. Secondary end points included the rates of restenosis (a binary variable) and major adverse cardiac events.
RESULTS: Multivessel disease was present in 80% of patients in both groups. Quantitative coronary angiography revealed no significant differences in baseline measures. At 6 months, angiography showed that the mean (+/-SD) in-segment late luminal loss was 0.74+/-0.86 mm in the uncoated-balloon group versus 0.03+/-0.48 mm in the coated-balloon group (P=0.002). A total of 10 of 23 patients (43%) in the uncoated-balloon group had restenosis, as compared with 1 of 22 patients (5%) in the coated-balloon group (P=0.002). At 12 months, the rate of major adverse cardiac events was 31% in the uncoated-balloon group and 4% in the coated-balloon group (P=0.01). This difference was primarily due to the need for target-lesion revascularization in six patients in the uncoated-balloon group (P=0.02).
CONCLUSIONS: Treatment of coronary in-stent restenosis with paclitaxel-coated balloon catheters significantly reduced the incidence of restenosis. These data suggest that the inhibition of restenosis by local drug delivery may not require stent implantation and sustained drug release at the site of injury. (ClinicalTrials.gov number, NCT00106587 [ClinicalTrials.gov].).

 

BACKGROUND: Treatment of in-stent restenosis with paclitaxel-coated balloon catheter as compared with plain balloon angioplasty has shown surprisingly low late lumen loss at 6 months and fewer major adverse cardiac events up to 2 years. We compared the efficacy and safety of a paclitaxel-coated balloon with a paclitaxel-eluting stent as the current standard of care.
METHODS AND RESULTS: One hundred thirty-one patients with coronary in-stent restenosis were randomly assigned to treatment by a paclitaxel-coated balloon (3 microg/mm2) or a paclitaxel-eluting stent. The main inclusion criteria encompassed diameter stenosis of>or =70% and<or =22 mm in length, with a vessel diameter of 2.5 to 3.5 mm. The primary end point was angiographic in-segment late lumen loss. Quantitative coronary angiography revealed no differences in baseline parameters. At 6 months follow-up, in-segment late lumen loss was 0.38+/-0.61 mm in the drug-eluting stent group versus 0.17+/-0.42 mm (P=0.03) in the drug-coated balloon group, resulting in a binary restenosis rate of 12 of 59 (20%) versus 4 of 57 (7%; P=0.06). At 12 months, the rate of major adverse cardiac events were 22% and 9%, respectively (P=0.08). This difference was primarily due to the need for target lesion revascularization in 4 patients (6%) in the coated-balloon group, compared with 10 patients (15%) in the stent group (P=0.15).
CONCLUSIONS: Treatment of coronary in-stent restenosis with the paclitaxel-coated balloon was at least as efficacious and as well tolerated as the paclitaxel-eluting stent. For the treatment of in-stent restenosis, inhibition of re-restenosis does not require a second stent implantation.

 

OBJECTIVE: We sought to compare the efficacy of drug-eluting balloons (DEB) and everolimus-eluting stents (EES) in patients with bare-metal stent (BMS) in-stent restenosis (ISR).
BACKGROUND: Treatment of patients with ISR remains a challenge.
METHODS: This was a prospective, multicenter, randomized trial comparing DEB and EES in patients with BMS-ISR. The primary end-point was minimal lumen diameter at 9-month follow-up.
RESULTS: 189 patients with BMS-ISR from 25 Spanish sites were included (95 allocated to DEB and 94 to EES). Procedural success was achieved in all patients. At late angiography (median 249 days, 92% of eligible patients) patients in the EES arm had a significantly larger minimal lumen diameter (2.36+0.6 vs 2.01+0.6 mm, p<0.001; absolute mean difference 0.35 mm 95%CI 0.16-0.53) and a lower % diameter stenosis (13+17% vs 25+20%, p<0.001). However, late loss (0.04+0.5 vs 0.14+0.5 mm, p=0.14) and binary restenosis rate (4.7 vs 9.5%, p=0.22) were very low and similar in both groups. Clinical follow-up (median 365 days) was obtained in all (100%) patients. The occurrence of the combined clinical outcome measure (cardiac death, myocardial infarction and target vessel revascularization) (6 vs 8%; HR:0.76;95%CI:0.26-2.18, p=0.6) and the need for target vessel revascularization (2 vs 6%; HR:0.32:0.07-1.59, p=0.17) were similar in the 2 groups.
CONCLUSIONS: In patients with BMS-ISR both DEB and EES provide excellent clinical results with a very low rate of clinical and angiographic recurrences. However, as compared with DEB, EES provide superior late angiographic findings.
CLINICAL TRIAL INFO: NCT01239953.

BACKGROUND: The best way to manage restenosis in patients who have previously received a drug-eluting stent is unknown. We investigated the efficacy of paclitaxel-eluting balloons (PEB), paclitaxel-eluting stents (PES), and balloon angioplasty in these patients.
METHODS: In this randomised, open-label trial, we enrolled patients older than 18 years with restenosis of at least 50% after implantation of any limus-eluting stent at three centres in Germany between Aug 3, 2009, and Oct 27, 2011. Patients were randomly assigned (1:1:1; stratified according to centre) to receive PEB, PES, or balloon angioplasty alone by means of sealed, opaque envelopes containing a computer-generated sequence. Patients and investigators were not masked to treatment allocation, but events and angiograms were assessed by individuals who were masked. The primary endpoint was diameter stenosis at follow-up angiography at 6-8 months. Primary analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00987324.
FINDINGS: We enrolled 402 patients, of whom 137 (34%) were assigned to PEB, 131 (33%) to PES, and 134 (33%) to balloon angioplasty. Follow-up angiography at 6-8 months was available for 338 (84%) patients. PEB was non-inferior to PES in terms of diameter stenosis (38·0% [SD 21·5]vs 37·4% [21·8]; difference 0·6%, one-sided 95% CI 4·9%; p(non-inferiority)=0·007; non-inferiority margin of 7%). Findings were consistent in per-protocol analysis (p(non-inferiority)=0·011). PEB and PES were superior to balloon angioplasty alone (54·1% [25·0]; p(superiority)<0·0001 for both comparisons). Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups.
INTERPRETATION: By obviating the need for additional stent implantation, PEB could be a useful treatment for patients with restenosis after implantation of a drug-eluting stent.
FUNDING: Deutsches Herzzentrum.

 

OBJECTIVE: To evaluate the clinical and angiographic outcome in patients with in-stent restenosis in small coronary arteries and repeat target lesion revascularisation.
DESIGN: Patients with in-stent restenosis in coronary arteries<or = 2.85 mm were eligible for the study and underwent target lesion revascularisation. Clinical and angiographic variables were assessed during a six month follow up period.
RESULTS: 73 patients with 79 lesions were treated by percutaneous transluminal coronary angioplasty (47%), excimer laser angioplasty (25%), or restenting (28%). The mean (SD) reference diameter before target lesion revascularisation was 2.12 (0.5) mm. Procedural success was achieved in all cases, but 57% of the patients had restenosis after six months. The rate of further restenosis was higher with laser angioplasty (78%) than with restenting (47%) or balloon angioplasty alone (49%, p<0.05).
CONCLUSIONS: Treatment for in-stent restenosis in small coronary arteries is feasible and safe, with a second restenosis rate comparable to large coronary artery series. The strategy of target lesion revascularisation influences further in-stent restenosis, with an increased rate with laser angioplasty compared with restenting and repeat dilatation alone.

 

OBJECTIVE: We examined long-term outcomes of patients with in-stent restenosis (ISR) who underwent different percutaneous interventions at the discretion of individual operators: balloon angioplasty (BA), repeat stent or rotational atherectomy (RA). We also examined long-term outcomes of patients with ISR who underwent coronary artery bypass surgery (CABG).
BACKGROUND: In-stent restenosis remains a challenging problem, and its optimal management is still unknown.
METHODS: Symptomatic patients (n = 510) with ISR were identified using cardiac catheterization laboratory data. Management for ISR included BA (169 patients), repeat stenting (117 patients), RA (107 patients) or CABG (117 patients). Clinical outcome events of interest included death, myocardial infarction, target vessel revascularization (TVR) and a combined end point of these major adverse cardiovascular events (MACE). Mean follow-up was 19+/-12 months (range = 6 to 61 months).
RESULTS: Patients with ISR treated with repeat stent had significantly larger average post-procedure minimal lumen diameter compared with BA or RA (3.3+/-0.4 mm vs. 3.0+/-0.4 vs. 2.9+/-0.5, respectively, p<0.05). Incidence of TVR and MACE were similar in the BA, stent and RA groups (39%, 40%, 33% for TVR and 43%, 40%, 33% for MACE, p = NS). Patients with diabetes who underwent RA had similar outcomes as patients without diabetes, while patients with diabetes who underwent BA or stent had worse outcomes than patients without diabetes. Patients who underwent CABG for ISR, mainly because of the presence of multivessel disease, had significantly better outcomes than any percutaneous treatment (8% for TVR and 23% for MACE).
CONCLUSIONS: In this large cohort of patients with ISR and in the subset of patients without diabetes, long-term outcomes were similar in the BA, repeat stent and RA groups. Tissue debulking with RA yielded better results only in diabetic patients. Bypass surgery for patients with multivessel disease and ISR provided the best outcomes.

 

BACKGROUND: In patients who develop in-stent restenosis, successful revascularization can be difficult to achieve using percutaneous methods. This study was designed to verify the surgical results in this setting and to evaluate the potential beneficial role of arterial bypass conduits.
METHODS AND RESULTS: Sixty consecutive coronary artery bypass patients with previous in-stent restenosis and 60 control cases were randomly assigned to receive an arterial conduit (either right internal thoracic or radial artery; study group) or a great saphenous vein graft (control group) on the first obtuse marginal artery to complete the surgical revascularization procedure. At a mean follow-up of 52+/-11 months, patients were reassessed clinically and by angiography. Freedom from clinical and instrumental evidence of ischemia recurrence was found in 19 of 60 subjects in the study group versus 45 of 60 in the control series (P=0.01). The results of the arterial grafts were excellent in both the study and control groups (right internal thoracic artery patency rate, 19 of 20 for both, and radial artery patency rate, 20 of 20 versus 19 of 20; P=0.99). Saphenous vein grafts showed lower patency rate than arterial grafts in both series and had extremely high failure rate in the study group (patency rate, 10 of 20 in the study group versus 18 of 20 in the control group; P=0.001). Use of venous graft was an independent predictor of failure in the study group, whereas hypercholesterolemia was associated with graft failure in both series.
CONCLUSIONS: Venous grafts have an high incidence of failure among cases who previously developed in-stent restenosis, whereas the use of arterial conduits can improve the angiographic and clinical results. Arterial grafts should probably be the first surgical choice in this patient population.

Background It is still unclear if patients treated for ISR may benefit from a long DAPT regimen.

Methods For the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications.

  • AD PMID 24161321
  • TI Prasugrel versus clopidogrel in patients with acute coronary syndromes.
  • AU Wiviott SD1, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators.
  • SO N Engl J Med. 2007 Nov 15;357(20):2001-15. Epub 2007 Nov 4.

BACKGROUND:

Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention.

METHODS:

To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding.

RESULTS:

The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002).

CONCLUSIONS:

In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)

The lumen diameter reduction after percutaneous coronary intervention (PCI) is well known as “restenosis”. This phenomenon is due to vessel remodeling/recoil in case of no-stent strategy or, in case of stent employ, “neointimal proliferation” that consists in an excessive tissue proliferation in the luminal surface of the stent otherwise by a further new-occurring atherosclerotic process called “neoatherosclerosis”. The exact incidence of in-stent restenosis (ISR) is not easy to determine caused by different clinical, angiographic and operative factors. In the pre-stent era the occurrence of restenosis ranged between 32-55% of all angioplasties, and drop to successively 17-41% in the bare metal stents (BMS) era. The advent of drug eluting stent (DES), especially 2nd generation, and drug-coated balloon (DCB) further reduce restenosis rate until <10%. We here review the main characteristics of this common complication of coronary interventions, from its pathogenesis to the most appropriate treatment strategy.

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The 16th annual EmTech MIT – A Place of Inspiration, October 18-20, 2016, Cambridge, MA

MIT Media Lab
Building E14
75 Amherst Street

(Corner of Ames and Amherst)
Cambridge, MA 02139

Conference Location: Entire 6th floor of Building E14

EmTech MIT Brings The Award-Winning Journalism of MIT Technology Review To Life

The 16th annual EmTech MIT gathers preeminent thought leaders, researchers and business leaders to examine the most significant themes in emerging technologies, including:

– Rethinking Energy

– Virtual Reality, Augmented Life

– Artificial intelligence

– Global Connectivity

– Engineering a Healthy Planet

– Spotlight talks on the 10 Breakthrough Technologies

– Celebration of the 2016 Innovators Under 35

ANNOUNCEMENT

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

pharma_bi-background0238

will cover in REAL TIME

The 16th annual EmTech MIT – A Place of Inspiration, October 18-20, 2016, Cambridge, MA

http://events.technologyreview.com/emtech/16/

In attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

@pharma_BI

@AVIVA1950

 All Speakers

SOURCE

http://events.technologyreview.com/emtech/16/#section-about

Featured Speakers

 

  • Nora
    Ayanian

    Gabilan Assistant Professor, University of Southern California

    2016 Innovator Under 35

  • Amir
    Banifatemi

    Prize Lead, X Prize

    Incentivizing Innovative Approaches & Collaboration in A.I.

  • Muyinatu
    Bell

    Assistant Professor, Johns Hopkins University

    2016 Innovator Under 35

  • Brian
    Bergstein

    Executive Editor, MIT Technology Review

  • Nessan
    Bermingham

    Chief Executive Officer, President and Founder, Intellia Therapeutics

    The Potential for Genome Editing Technology to Transform Medicine

  • Dinesh
    Bharadia

    Postdoctoral Associate, MIT CSAIL

    2016 Innovator Under 35

  • Heather
    Bowerman

    CEO & Founder, Dot Laboratories

    2016 Innovator Under 35

  • Elizabeth
    Bramson-Boudreau

    Chief Operating Officer, MIT Technology Review

  • Qing
    Cao

    Research Staff Member, IBM T.J. Watson Research Center

    2016 Innovator Under 35

  • Jagdish
    Chaturvedi

    Director, Clinical Innovations, InnAccel

    2016 Innovator Under 35

  • David
    Cox

    Assistant Professor of Molecular and Cellular Biology and of Computer Science, Harvard University

    Building Computer Vision Systems Inspired by the Brain

  • Tom
    Davenport

    President’s Distinguished Professor of Information Technology & Management, Babson College

    Presented by RAGE Frameworks

  • Stefano
    Domenicali

    CEO, Automobili Lamborghini

    Presented by the Italian Trade Agency

  • Kevin
    Esvelt

    Assistant Professor, MIT Media Lab

    The Technology Driving Gene Drives

  • Vivian
    Ferry

    Assistant Professor, University of Minnesota

    2016 Innovator Under 35

  • Wei
    Gao

    Postdoctoral Fellow, University of California, Berkeley

    2016 Innovator Under 35

  • Dileep
    George

    Cofounder, Vicarious

    Artificial Intelligence At Work

  • Shyam
    Gollakota

    Assistant Professor, University of Washington

    10 Breakthrough Technologies of 2016: Power from the Air

  • Meron
    Gribetz

    CEO, Meta

    2016 Innovator Under 35

  • Jiawei
    Gu

    Cofounder, Ling Robotics

    2016 Innovator Under 35

  • Rachel
    Haot

    Managing Director, 1776

    Incubating Technical Solutions with Global Impact

  • Alex
    Hegyi

    Member of Research Staff, PARC

    2016 Innovator Under 35

  • Katherine
    High

    Cofounder, President and Chief Scientific Officer, Spark Therapeutics

    Gene Therapy: A New Era of Medicine

  • Christine
    Ho

    CEO, Imprint Energy, Inc.

    2016 Innovator Under 35

  • Ehsan
    Hoque

    Assistant Professor, University of Rochester

    2016 Innovator Under 35

  • Solomon
    Hsiang

    Chancellor’s Associate Professor of Public Policy, University of California, Berkeley

    Addressing the Effects of Climate Change

  • Karl
    Iagnemma

    CEO and Cofounder, nuTonomy

    Intelligent Machines: Autonomous Cars

  • Sangbae
    Kim

    Associate Professor of Mechanical Engineering, MIT

    Robots at Work

  • Samay
    Kohli

    Chief Executive Officer, GreyOrange

    2016 Innovator Under 35

  • Kendra
    Kuhl

    CTO, Opus 12

    2016 Innovator Under 35

  • Maithilee
    Kunda

    Assistant Professor, Vanderbilt University

    2016 Innovator Under 35

  • Stephanie
    Lampkin

    Founder & CEO, Blendoor

    2016 Innovator Under 35

  • Desmond
    Loke

    Assistant Professor, Singapore University of Technology and Design

    2016 Innovator Under 35

  • Evan
    Macosko

    Instructor, Harvard Medical School

    2016 Innovator Under 35

  • Yael
    Maguire

    Engineering Director, Facebook Connectivity Lab

    Expanding the Global Impact of Internet Connectivity

  • Vikram
    Mahidhar

    SVP, Artificial Intelligence Solutions, RAGE Frameworks

    Presented by RAGE Frameworks

  • Marcela
    Maus

    Director of Cellular Immunotherapy, Massachusetts General Hospital Cancer Center

    The Promise of Cancer Immunotherapy

  • Pranav
    Mistry

    Global Vice President of Research, Samsung

    Envisioning What’s Next for Virtual Reality

  • Jason
    Pontin

    Editor in Chief and Publisher, MIT Technology Review

  • Ramesh
    Raskar

    Director, MIT Media Lab Camera Culture Group

    Presented by Lemelson-MIT

  • Alberto Maria
    Sacchi

    Board Member & Past President, Federmacchine

    Presented by the Italian Trade Agency

  • Don
    Sadoway

    Professor, Materials Science & Engineering, MIT

    Providing Power for a Growing Global Population

  • Ruslan
    Salakhutdinov

    Associate Professor, Carnegie Mellon University

    The Promise and Limitations of Machine Learning

  • Kelly
    Sanders

    Assistant Professor, University of Southern California

    2016 Innovator Under 35

  • Michele
    Scannavini

    President, Italian Trade Agency

    Presented by the Italian Trade Agency

  • Stefanie
    Tellex

    Assistant Professor, Computer Science, Brown University

    10 Breakthrough Technologies of 2016: Robots That Teach Each Other

  • Ronaldo
    Tenorio

    CEO, Hand Talk

    2016 Innovator Under 35

  • Sonia
    Vallabh

    PhD Student, Prion Scientist, Broad Institute

    2016 Innovator Under 35

  • Cyrus
    Vance Jr.

    Manhattan District Attorney, Manhattan District Attorney’s Office

    Security & Privacy in the Connected Era

  • Oriol
    Vinyals

    Research Scientist, Google DeepMind

    2016 Innovator Under 35

  • Aleksandra
    Vojvodic

    Assistant Professor, University of Pennsylvania

    2016 Innovator Under 35

  • Padmasree
    Warrior

    CEO, NextEV

    Imagining Clean, Connected Transportation

  • Jean
    Yang

    Assistant Professor, Carnegie Mellon University

    2016 Innovator Under 35

  • Yihui
    Zhang

    Associate Professor, Tsinghua University

    2016 Innovator Under 35

  • Jia
    Zhu

    Professor, Nanjing University

    2016 Innovator Under 35

 

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New e-Book TITLES forthcoming on Amazon.com in 2017-2018 from LPBI Group’s BioMed e-Series – Forthcoming COVER PAGES

Editor-in-Chief, Aviva Lev-Ari, PhD, RN

 

BioMed e-Series

https://pharmaceuticalintelligence.com/biomed-e-books/

BioMed e-Series

WE ARE ON AMAZON.COM

http://www.amazon.com/dp/B00DINFFYC

http://www.amazon.com/dp/B018Q5MCN8

http://www.amazon.com/dp/B018PNHJ84

http://www.amazon.com/dp/B018DHBUO6

http://www.amazon.com/dp/B013RVYR2K

http://www.amazon.com/dp/B012BB0ZF0

http://www.amazon.com/dp/B019UM909A

http://www.amazon.com/dp/B019VH97LU

https://www.amazon.com/dp/B075CXHY1B

https://www.amazon.com/dp/B076HGB6MZ

https://www.amazon.com/dp/B078313281

Slide4

FORTHCOMING

CANCER – Volume Two on Amazon.com

http://www.amazon.com/dp/B019VH97LU

GENOMICS – Volume Two – 2018

flyer3forApril2016BioWorld

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 cover volume 6 Series Acover volume 5 Series A
final series E covers volumes 1_4-vol4final series E covers volumes 1_4-vol1final series E covers volumes 1_4-vol2

BioMedical e-Books e-Series:

Cardiovascular, Genomics, Cancer, BioMed, Patient Centered Medicine

https://pharmaceuticalintelligence.com/biomed-e-books/

2013 e-Book on Amazon.com

  • Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

2015 e-Book on Amazon.com

 

http://www.amazon.com/dp/B012BB0ZF0

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

  • Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

  • Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics, on Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

  • Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

  • Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

2017 e-Book on Amazon.com

  • Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2) – on Amazon since 5/18/2017

http://www.amazon.com/dp/B071VQ6YYK

  • The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since September 4, 2017

https://www.amazon.com/dp/B075CXHY1B

  • The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures – on Amazon.com since 10/16/2017

https://www.amazon.com/dp/B076HGB6MZ

  • Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders – Available on Kindle Store @ Amazon.com since 12/9/2017

https://www.amazon.com/dp/B078313281

 

Series E: Patient-centered Medicine

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: The VOICES of Patients, HealthCare Providers, Care Givers and Families: Personal Experience with Critical Care and Invasive Medical Procedures – COMPLETED

Author, Curator and Editor: Larry H Bernstein, MD, FCAP and Gail Thornton, PhD(c)

https://www.amazon.com/dp/B076HGB6MZ

 

Volume 2: Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders – 

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Available on Kindle Store @ Amazon.com since 12/9/2017

https://www.amazon.com/dp/B078313281

 

Volume 3: Milestones in Physiology & Discoveries in Medicine and Genomics, on Amazon.com since 12/27/2015

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

http://www.amazon.com/dp/B019VH97LU

 

Volume 4:  Medical 3D BioPrinting – The Revolution in Medicine – Format Conversion Satge

Editors:  Dr. Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Scheduled for publication in 2017

Forthcoming COVER PAGES

Series A: Volume 5: Pharmacology-Therapy of Cardiovascular Diseases 

cover volume 5 Series A

Series A: Volume 6: Interventional Cardiology and Cardiac Surgery for Disease Diagnosis and Guidance of Treatment

cover volume 6 Series A

 

Series B: Volume 2: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

genomicsinpersonalizedmedvol1and2Apr2016-page2

 

 

 

 

 

Series E:

 

Volume 4:  Medical 3D BioPrinting – The Revolution in Medicine

final series E covers volumes 1_4-vol4

 

 

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Protein profiling in cancer and metabolic diseases

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Deep Protein Profiling Key

Company has encouraged by two recent reports that emphasise the importance of protein profiling to improve outcomes in cancer treatment.

http://www.technologynetworks.com/Proteomics/news.aspx?ID=190145

Proteome Sciences plc has strongly encouraged by two recent reports that emphasise the importance of protein profiling to improve outcomes in cancer treatment. These highlight the growing need for more detailed, personal assessment of protein profiles to improve the management of cancer treatment.

In the first study two groups from University College London and Cancer Research UK demonstrated that genetic mutations in cancer can lead to changes in the proteins on the cell surface1. These are new sequences which are seen as foreign by the body’s immune system and, with appropriate immunotherapy, the level of response in lung cancer was greatly enhanced.

However many of the patients with these types of mutations unfortunately still did not respond which highlighted the need for deeper analysis of the protein expression in tumours in order to better appreciate the mechanisms that contribute to treatment failure.

The second study, led by Professor Nigel Bundred of Manchester University, reported that use of two drugs that act on the same breast cancer target, an over-expressing protein called Her-2, were able to eradicate detectable tumours in around 10% of those treated in just 11 days, with 87% of those treated having a proteomic change indicating cells had stopped growing and/or cell death had increased2.

Whilst these results appear very promising it is worth noting that the over-expressing Her-2 target is only present in about 20% of breast tumours meaning this combination therapy was successful in clearing tumours in just 2% of the total breast cancer population.

Dr. Ian Pike, Chief Operating Officer of Proteome Sciences commented, “Both these recent studies should rightly be recognised as important steps forward towards better cancer treatment. However, in order to overcome the limitations of current drug therapy programs, a much deeper and more comprehensive analysis of the complex protein networks that regulate tumour growth and survival is required and will be essential to achieve a major advance in the battle to treat cancer.

“Our SysQuant® workflows provide that solution. As an example, in pancreatic cancer3 we have successfully mapped the complex network of regulatory processes and demonstrate the ability to devise personalised treatment combinations on an individual basis for each patient. A retrospective study with SysQuant® to predict response to the targeted drug Sorafenib in liver cancer is in process and we are planning further prospective trials to guide personalised treatment selection in liver cancer.

“We are already delivering systems-wide biology solutions through SysQuant® and TMTcalibrator™ programs to our clients that are generating novel biological data and results using more sensitive profiling that are helping them to better understand their drug development programs and to provide new biomarkers for tracking patient response in clinical trials.

“We are strongly positioned to deliver more comprehensive analysis of proteins and cellular pathways across other areas of disease and in particular to extend the use of SysQuant® with other leading cancer research groups in liver and other cancers.”

Proteome Sciences has also expanded its offering in personalised medicine through the use of its TMTcalibrator™ technology to uniquely identify protein biomarkers that reveal active cancer and other disease processes in body fluid samples. The importance of these ‘mechanistic’ biomarkers is that they are essential to monitor that drugs are being effective and that they can be used as early biomarkers of disease recurrence.

Using SysQuant® and TMTcalibrator™, Proteome Sciences can deliver more comprehensive analysis and provide unparalleled levels of sensitivity and breadth of coverage of the proteome, enabling faster, more efficient drug development and more accurate disease diagnosis.

 

Discovering ‘Outlier’ Enzymes

Researchers at TSRI and Salk Institute have discovered ‘Outlier’ enzymes that could offer new targets to treat type 2 diabetes and inflammatory disorders.

A team led by scientists at The Scripps Research Institute (TSRI) and the Salk Institute for Biological Studies have discovered two enzymes that appear to play a role in metabolism and inflammation—and might someday be targeted with drugs to treat type 2 diabetes and inflammatory disorders. The discovery is unusual because the enzymes do not bear a resemblance—in their structures or amino-acid sequences—to any known class of enzymes.

The team of scientists nevertheless identified them as “outlier” members of the serine/threonine hydrolase class, using newer techniques that detect biochemical activity. “A huge fraction of the human ‘proteome’ remains uncharacterized, and this paper shows how chemical approaches can be used to uncover proteins of a given functionality that have eluded classification based on sequence or predicted structure,” said co-senior author Benjamin F. Cravatt, chair of TSRI’s Department of Chemical Physiology.

“In this study, we found two genes that control levels of lipids with anti-diabetic and anti-inflammatory activity, suggesting exciting targets for diabetes and inflammatory diseases,” said co-senior author Alan Saghatelian, who holds the Dr. Frederik Paulsen Chair at the Salk Institute. The study, which appeared as a Nature Chemical Biology Advance Online Publication on March 28, 2016, began as an effort in the Cravatt laboratory to discover and characterize new serine/threonine hydrolases using fluorophosphonate (FP) probes—molecules that selectively bind and, in effect, label the active sites of these enzymes.

Pulling FP-binding proteins out of the entire proteome of test cells and identifying them using mass spectrometry techniques, the team matched nearly all to known hydrolases. The major outlier was a protein called androgen-induced gene 1 protein (AIG1). The only other one was a distant cousin in terms of sequence, a protein called ADTRP. “Neither of these proteins had been characterized as an enzyme; in fact, there had been little functional characterization of them at all,” said William H. Parsons, a research associate in the Cravatt laboratory who was co-first author of the study.

Experiments on AIG1 and ADTRP revealed that they do their enzymatic work in a unique way. “It looks like they have an active site that is novel—it had never been described in the literature,” said Parsons. Initial tests with panels of different enzyme inhibitors showed that AIG1 and ADTRP are moderately inhibited by inhibitors of lipases—enzymes that break down fats and other lipids. But on what specific lipids do these newly discovered outlier enzymes normally work?

At the Salk Institute, the Saghatelian laboratory was investigating a class of lipids it had discovered in 2014. Known as fatty acid esters of hydroxy fatty acids (FAHFAs), these molecules showed strong therapeutic potential. Saghatelian and his colleagues had found that boosting the levels of one key FAHFA lipid normalizes glucose levels in diabetic mice and also reduces inflammation.

“[Ben Cravatt’s] lab was screening panels of lipids to find the ones that their new enzymes work on,” said Saghatelian, who is a former research associate in the Cravatt laboratory. “We suggested they throw FAHFAs in there—and these turned out to be very good substrates.” The Cravatt laboratory soon developed powerful inhibitors of the newly discovered enzymes, and the two labs began working together, using the inhibitors and genetic techniques to explore the enzymes’ functions in vitro and in cultured cells.

Co-first author Matthew J. Kolar, an MD-PhD student, performed most of the experiments in the Saghatelian lab. The team concluded that AIG1 and ADTRP, at least in the cell types tested, appear to work mainly to break down FAHFAs and not any other major class of lipid. In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies.

“Our prediction,” said Saghatelian, “is that if FAHFAs do what we think they’re doing, then using an enzyme inhibitor to block their degradation would make FAHFA levels go up and should thus reduce inflammation as well as improve glucose levels and insulin sensitivity.” The two labs are now collaborating on further studies of the new enzymes—and the potential benefits of inhibiting them—in mouse models of diabetes, inflammation and autoimmune disease.

“One of the neat things this study shows,” said Cravatt, “is that even for enzyme classes as well studied as the hydrolases, there may still be hidden members that, presumably by convergent evolution, arrived at that basic enzyme mechanism despite sharing no sequence or structural homology.”

Other co-authors of the study, “AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs,” were Siddhesh S. Kamat, Armand B. Cognetta III, Jonathan J. Hulce and Enrique Saez, of TSRI; and co-senior author Barbara B. Kahn of Beth Israel Deaconess Medical Center and Harvard Medical School

 

New Weapon Against Breast Cancer

Molecular marker in healthy tissue can predict a woman’s risk of getting the disease, research says.

Harvard Stem Cell Institute (HSCI) researchers at Dana-Farber Cancer Institute (DFCI) and collaborators at Brigham and Women’s Hospital (BWH) have identified a molecular marker in normal breast tissue that can predict a woman’s risk for developing breast cancer, the leading cause of death in women with cancer worldwide.

The work, led by HSCI principal faculty member Kornelia Polyak and Rulla Tamimi of BWH, was published in an early online release and in the April 1 issue of Cancer Research.

The study builds on Polyak’s earlier research finding that women already identified as having a high risk of developing cancer — namely those with a mutation called BRCA1 or BRCA2 — or women who did not give birth before their 30s had a higher number of mammary gland progenitor cells.

In the latest study, Polyak, Tamimi, and their colleagues examined biopsies, some taken as many as four decades ago, from 302 participants in the Nurses’ Health Study and the Nurses’ Health Study II who had been diagnosed with benign breast disease. The researchers compared tissue from the 69 women who later developed cancer to the tissue from the 233 women who did not. They found that women were five times as likely to develop cancer if they had a higher percentage of Ki67, a molecular marker that identifies proliferating cells, in the cells that line the mammary ducts and milk-producing lobules. These cells, called the mammary epithelium, undergo drastic changes throughout a woman’s life, and the majority of breast cancers originate in these tissues.

Doctors already test breast tumors for Ki67 levels, which can inform decisions about treatment, but this is the first time scientists have been able to link Ki67 to precancerous tissue and use it as a predictive tool.

“Instead of only telling women that they don’t have cancer, we could test the biopsies and tell women if they were at high risk or low risk for developing breast cancer in the future,” said Polyak, a breast cancer researcher at Dana-Farber and co-senior author of the paper.

“Currently, we are not able to do a very good job at distinguishing women at high and low risk of breast cancer,” added co-senior author Tamimi, an associate professor at the Harvard T.H. Chan School of Public Health and Harvard Medical School. “By identifying women at high risk of breast cancer, we can better develop individualized screening and also target risk reducing strategies.”

To date, mammograms are the best tool for the early detection, but there are risks associated with screening. False positive and negative results and over-diagnosis could cause psychological distress, delay treatment, or lead to overtreatment, according to the National Cancer Institute (NCI).

Mammography machines also use low doses of radiation. While a single mammogram is unlikely to cause harm, repeated screening can potentially cause cancer, though the NCI writes that the benefits “nearly always outweigh the risks.”

“If we can minimize unnecessary radiation for women at low risk, that would be good,” said Tamimi.

Screening for Ki67 levels would “be easy to apply in the current setting,” said Polyak, though the researchers first want to reproduce the results in an independent cohort of women.

 

AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs

William H ParsonsMatthew J Kolar, …., Barbara B KahnAlan Saghatelian & Benjamin F Cravatt

Nature Chemical Biology 28 March 2016                    http://dx.doi.org:/10.1038/nchembio.2051

Enzyme classes may contain outlier members that share mechanistic, but not sequence or structural, relatedness with more common representatives. The functional annotation of such exceptional proteins can be challenging. Here, we use activity-based profiling to discover that the poorly characterized multipass transmembrane proteins AIG1 and ADTRP are atypical hydrolytic enzymes that depend on conserved threonine and histidine residues for catalysis. Both AIG1 and ADTRP hydrolyze bioactive fatty acid esters of hydroxy fatty acids (FAHFAs) but not other major classes of lipids. We identify multiple cell-active, covalent inhibitors of AIG1 and show that these agents block FAHFA hydrolysis in mammalian cells. These results indicate that AIG1 and ADTRP are founding members of an evolutionarily conserved class of transmembrane threonine hydrolases involved in bioactive lipid metabolism. More generally, our findings demonstrate how chemical proteomics can excavate potential cases of convergent or parallel protein evolution that defy conventional sequence- and structure-based predictions.

Figure 1: Discovery and characterization of AIG1 and ADTRP as FP-reactive proteins in the human proteome.

 

http://www.nature.com/nchembio/journal/vaop/ncurrent/carousel/nchembio.2051-F1.jpg

(a) Competitive ABPP-SILAC analysis to identify FP-alkyne-inhibited proteins, in which protein enrichment and inhibition were measured in proteomic lysates from SKOV3 cells treated with FP-alkyne (20 μM, 1 h) or DMSO using the FP-biotin…

 

  1. Willems, L.I., Overkleeft, H.S. & van Kasteren, S.I. Current developments in activity-based protein profiling. Bioconjug. Chem. 25, 11811191 (2014).
  2. Niphakis, M.J. & Cravatt, B.F. Enzyme inhibitor discovery by activity-based protein profiling.Annu. Rev. Biochem. 83, 341377 (2014).
  3. Berger, A.B., Vitorino, P.M. & Bogyo, M. Activity-based protein profiling: applications to biomarker discovery, in vivo imaging and drug discovery. Am. J. Pharmacogenomics 4,371381 (2004).
  4. Liu, Y., Patricelli, M.P. & Cravatt, B.F. Activity-based protein profiling: the serine hydrolases.Proc. Natl. Acad. Sci. USA 96, 1469414699 (1999).
  5. Simon, G.M. & Cravatt, B.F. Activity-based proteomics of enzyme superfamilies: serine hydrolases as a case study. J. Biol. Chem. 285, 1105111055 (2010).
  6. Bachovchin, D.A. et al. Superfamily-wide portrait of serine hydrolase inhibition achieved by library-versus-library screening. Proc. Natl. Acad. Sci. USA 107, 2094120946 (2010).
  7. Jessani, N. et al. A streamlined platform for high-content functional proteomics of primary human specimens. Nat. Methods 2, 691697 (2005).
  8. Higa, H.H., Diaz, S. & Varki, A. Biochemical and genetic evidence for distinct membrane-bound and cytosolic sialic acid O-acetyl-esterases: serine-active-site enzymes. Biochem. Biophys. Res. Commun. 144, 10991108 (1987).

Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesteras-1 inhibitors

Proc Natl Acad Sci U S A. 2011 Apr 26; 108(17): 6811–6816.    doi:  10.1073/pnas.1015248108
National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.

Protein phosphorylation is a pervasive and dynamic posttranslational protein modification in eukaryotic cells. In mammals, more than 500 protein kinases catalyze the phosphorylation of serine, threonine, and tyrosine residues on proteins (1). A much more limited number of phosphatases are responsible for reversing these phosphorylation events (2). For instance, protein phosphatase 2A (PP2A) and PP1 are thought to be responsible together for > 90% of the total serine/threonine phosphatase activity in mammalian cells (3). Specificity is imparted on PP2A activity by multiple mechanisms, including dynamic interactions between the catalytic subunit (C) and different protein-binding partners (B subunits), as well as a variety of posttranslational chemical modifications (2, 4). Within the latter category is an unusual methylesterification event found at the C terminus of the catalytic subunit of PP2A that is introduced and removed by a specific methyltransferase (leucine carbxoylmethyltransferase-1 or LCMT1) (5, 6) and methylesterase (protein phosphatase methylesterase-1 or PME-1) (7), respectively (Fig. 1A). PP2A carboxymethylation (hereafter referred to as “methylation”) has been proposed to regulate PP2A activity, at least in part, by modulating the binding interaction of the C subunit with various regulatory B subunits (810). A predicted outcome of these shifts in subunit association is the targeting of PP2A to different protein substrates in cells. PME-1 has also been hypothesized to stabilize inactive forms of nuclear PP2A (11), and recent structural studies have shed light on the physical interactions between PME-1 and the PP2A holoenzyme (12).

There were several keys to the success of our probe development effort. First, screening for inhibitors of PME-1 benefited from the fluopol-ABPP technology, which circumvented the limited throughput of previously described substrate assays for this enzyme. Second, we were fortunate that the NIH compound library contained several members of the ABL class of small molecules. These chiral compounds, which represent an academic contribution to the NIH library, occupy an unusual portion of structural space that is poorly accessed by commercial compound collections. Although at the time of their original synthesis (23) it may not have been possible to predict whether these ABLs would show specific biological activity, their incorporation into the NIH library provided a forum for screening against many proteins and cellular targets, culminating in their identification as PME-1 inhibitors. We then used advanced chemoproteomic assays to confirm the remarkable selectivity displayed by ABLs for PME-1 across (and beyond) the serine hydrolase superfamily. That the mechanism for PME-1 inhibition involves acylation of the enzyme’s conserved serine nucleophile (Fig. 3) suggests that exploration of a more structurally diverse set of ABLs might uncover inhibitors for other serine hydrolases. In this way, the chemical information gained from a single high-throughput screen may be leveraged to initiate probe development programs for additional enzyme targets.

Projecting forward, this research provides an example of how public small-molecule screening centers can serve as a portal for spawning academic collaborations between chemical biology and synthetic chemistry labs. By continuing to develop versatile high-throughput screens and combining them with a small-molecule library of expanding structural diversity conferred by advanced synthetic methodologies, academic biologists and chemists are well-positioned to collaboratively deliver pharmacological probes for a wide range of proteins and pathways in cell biology.

 

New weapon against breast cancer

Molecular marker in healthy tissue can predict a woman’s risk of getting the disease, research says

April 6, 2016 | Popular
BRC_Cancer605

 

New Group of Aging-Related Proteins Discovered

http://www.genengnews.com/gen-news-highlights/new-group-of-aging-related-proteins-discovered/81252599/

Scientists have discovered a group of six proteins that may help to divulge secrets of how we age, potentially unlocking new insights into diabetes, Alzheimer’s, cancer, and other aging-related diseases.

The proteins appear to play several roles in our bodies’ cells, from decreasing the amount of damaging free radicals and controlling the rate at which cells die to boosting metabolism and helping tissues throughout the body respond better to insulin. The naturally occurring amounts of each protein decrease with age, leading investigators to believe that they play an important role in the aging process and the onset of diseases linked to older age.

The research team led by Pinchas Cohen, M.D., dean and professor of the University of Southern California Leonard Davis School of Gerontology, identified the proteins and observed their origin from mitochondria and their game-changing roles in metabolism and cell survival. This latest finding builds upon prior research by Dr. Cohen and his team that uncovered two significant proteins, humanin and MOTS-c, hormones that appear to have significant roles in metabolism and diseases of aging.

Unlike most other proteins, humanin and MOTS-c are encoded in mitochondria. Dr. Cohen’s team used computer analysis to see if the part of the mitochondrial genome that provides the code for humanin was coding for other proteins as well. The analysis uncovered the genes for six new proteins, which were dubbed small humanin-like peptides, or SHLPs, 1 through 6 (pronounced “schlep”).

After identifying the six SHLPs and successfully developing antibodies to test for several of them, the team examined both mouse tissues and human cells to determine their abundance in different organs as well as their functions. The proteins were distributed quite differently among organs, which suggests that the proteins have varying functions based on where they are in the body. Of particular interest is SHLP 2, according to Dr. Cohen.  The protein appears to have insulin-sensitizing, antidiabetic effects as well as neuroprotective activity that may emerge as a strategy to combat Alzheimer’s disease. He added that SHLP 6 is also intriguing, with a unique ability to promote cancer cell death and thus potentially target malignant diseases.

Proteins That May Protect Against Age Related Illnesses Discovered

 

The cell proliferation antigen Ki-67 organises heterochromatin

 Michal Sobecki, 

Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.

 

A protein called Ki-67 is only produced in actively dividing cells, where it is located in the nucleus – the structure that contains most of the cell’s DNA. Researchers often use Ki-67 as a marker to identify which cells are actively dividing in tissue samples from cancer patients, and previous studies indicated that Ki-67 is needed for cells to divide. However, the exact role of this protein was not clear. Before cells can divide they need to make large amounts of new proteins using molecular machines called ribosomes and it has been suggested that Ki-67 helps to produce ribosomes.

Now, Sobecki et al. used genetic techniques to study the role of Ki-67 in mice. The experiments show that Ki-67 is not required for cells to divide in the laboratory or to make ribosomes. Instead, Ki-67 alters the way that DNA is packaged in the nucleus. Loss of Ki-67 from mice cells resulted in DNA becoming less compact, which in turn altered the activity of genes in those cells.

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Glycobiology advances

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Evolution of the Glycobiology Space

The Nascent Stage of another Omics Field with Biomarker and Therapeutic Potential

Enal Razvi, Ph.D. , Gary Oosta, Ph.D

http://www.genengnews.com/insight-and-intelligence/the-evolution-of-the-glycobiology-space/77900638/

 

The Evolution of the Glycobiology Space

 

Glycobiology is an important field of study with medical applications because it is known that tumor cells alter their glycosylation pattern, which may contribute to their metastatic potential as well as potential immune evasion. [iStock/© vjanez]    http://www.genengnews.com/media/images/AnalysisAndInsight/Apr12_2016_iStock_41612310_PlasmaMembraneOfACell1211657142.jpg

There is growing interest in the field of glycobiology given the fact that epitopes with physiological and pathological relevance have glyco moieties.  We believe that another “omics” revolution is on the horizon—the study of the glyco modifications on the surface of cells and their potential as biomarkers and therapeutic targets in many disease classes. Not much industry tracking of this field has taken place. Thus, we sought to map this landscape by examining the entire ensemble of academic publications in this space and teasing apart the trends operative in this field from a qualitative and quantitative perspective. We believe that this methodology of en masse capture and publication and annotation provides an effective approach to evaluate this early-stage field.

Identifiation and Growth of Glycobiology Publications

http://www.genengnews.com/Media/images/AnalysisAndInsight/thumb_April12_2016_SelectBiosciences_Figure11935315421.jpg

For this article, we identified 7000 publications in the broader glycobiology space and analyzed them in detail.  It is important to frame glycobiology in the context of genomics and proteomics as a means to assess the scale of the field. Figure 1 presents the relative sizes of these fields as assessed by publications in from 1975 to 2015.

Note that the relative scale of genomics versus proteomics and glycobiology/glycomics in this graph strongly suggests that glycobiology is a nascent space, and thus a driver for us to map its landscape today and as it evolves over the coming years.

Figure 2. (A) Segmentation of the glycobiology landscape. (B) Glycobiology versus glycomics publication growth.

 

http://www.genengnews.com/Media/images/AnalysisAndInsight/thumb_April12_2016_SelectBiosciences_Figure2ab1917013624.jpg

To examine closely the various components of the glycobiology space, we segmented the publications database, presented in Figure 2A. Note the relative sizes and growth rates (slopes) of the various segments.

Clearly, glycoconjugates currently are the majority of this space and account for the bulk of the publications.  Glycobiology and glycomics are small but expanding and therefore can be characterized as “nascent market segments.”  These two spaces are characterized in more detail in Figure 2B, which presents their publication growth rates.

Note the very recent increased attention directed at these spaces and hence our drive to initiate industry coverage of these spaces. Figure 2B presents the overall growth and timeline of expansion of these fields—especially glycobiology—but it provides no information about the qualitative nature of these fields.

Focus of Glycobiology Publications

http://www.genengnews.com/Media/images/AnalysisAndInsight/April12_2016_SelectBiosciences_Figure2c1827601892.jpg

Figure 2C. Word cloud based on titles of publications in the glycobiology and glycomics spaces.

To understand the focus of publications in this field, and indeed the nature of this field, we constructed a word cloud based on titles of the publications that comprise this space presented in Figure 2C.

There is a marked emphasis on terms such as oligosaccharides and an emphasis on cells (this is after all glycosylation on the surface of cells). Overall, a pictorial representation of the types and classes of modifications that comprise this field emerge in this word cloud, demonstrating the expansion of the glycobiology and to a lesser extent the glycomics spaces as well as the character of these nascent but expanding spaces.

Characterization of the Glycobiology Space in Journals

Figure 3A. Breakout of publications in the glycobiology/glycomics fields.   http://www.genengnews.com/Media/images/AnalysisAndInsight/April12_2016_SelectBiosciences_Figure3a_5002432117316.jpg
Having framed the overall growth of the glycobiology field, we wanted to understand its structure and the classes of researchers as well as publications that comprise this field. To do this, we segmented the publications that constitute this field into the various journals in which glycobiology research is published. Figure 3A presents the breakout of publications by journal to illustrate the “scope” of this field.

The distribution of glycobiology publications across the various journals suggests a very concentrated marketplace that is very technically focused. The majority of the publications segregate into specialized journals on this topic, a pattern very indicative of a field in the very early stages of development—a truly nascent marketplace.

http://www.genengnews.com/Media/images/AnalysisAndInsight/thumb_April12_2016_SelectBiosciences_Figure3b1012091061.jpg

Figure 3B. Origin of publications in the glycobiology/glycomics fields.
We also sought to understand the “origin” of these publications—the breakout between academic- versus industry-derived journals. Figure 3B presents this breakout and shows that these publications are overwhelmingly (92.3%) derived from the academic sector. This is again a testimonial to the early nascent nature of this marketplace without significant engagement by the commercial sector and therefore is an important field to characterize and track from the ground up.

Select Biosciences, Inc. further analyzed the growth trajectory of the glycobiology papers in Figure 3C as a means to examine closely the publications trajectory. Although there appears to be some wobble along the way, overall the trajectory is upward, and of late it is expanding significantly.

In Summary

Figure 3C. Trajectory of the glycobiology space.   http://www.genengnews.com/Media/images/AnalysisAndInsight/April12_2016_SelectBiosciences_Figure3c1236921793.jpg
Glycobiology is the study of what coats living cells—glycans, or carbohydrates, and glycoconjugates. This is an important field of study with medical applications because it is known that tumor cells alter their glycosylation pattern, which may contribute to their metastatic potential as well as potential immune evasion.

At this point, glycobiology is largely basic research and thus it pales in comparison with the field of genomics. But in 10 years, we predict the study of glycobiology and glycomics will be ubiquitous and in the mainstream.

We started our analysis of this space because we’ve been focusing on many other classes of analytes, such as microRNAs, long-coding RNAs, oncogenes, tumor suppressor genes, etc., whose potential as biomarkers is becoming established. Glycobiology, on the other hand, represents an entire new space—a whole new category of modifications that could be analyzed for diagnostic potential and perhaps also for therapeutic targeting.

Today, glycobiology and glycomics are where genomics was at the start of the Human Genome Project. They respresent a nascent space and with full headroom for growth. Select Biosciences will continue to track this exciting field for research developments as well as development of biomarkers based on glyco-epitopes.

Enal Razvi, Ph.D., conducted his doctoral work on viral immunology and subsequent to receiving his Ph.D. went on to the Rockefeller University in New York to serve as Aaron Diamond Post-doctoral fellow under Professor Ralph Steinman [Nobel Prize Winner in 2011 for his discovery of dendritic cells in the early-70s with Zanvil Cohn]. Subsequently, Dr. Razvi completed his research fellowship at Harvard Medical School. For the last two decades Dr. Razvi has worked with small and large companies and consulted for more than 100 clients worldwide. He currently serves as Biotechnology Analyst and Managing Director of SelectBio U.S. He can be reached at enal@selectbio.us. Gary M. Oosta holds a Ph.D. in Biophysics from Massachusetts Institute of Technology and a B.A. in Chemistry from E. Mich. Univ. He has 25 years of industrial research experience in various technology areas including medical diagnostics, thin-layer coating, bio-effects of electromagnetic radiation, and blood coagulation. Dr. Oosta has authored 20 technical publications and is an inventor on 77 patents worldwide. In addition, he has managed research groups that were responsible for many other patented innovations. Dr. Oosta has a long-standing interest in using patents and publications as strategic technology indicators for future technology selection and new product development. To enjoy more articles like this from GEN, click here to subscribe now!

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When the cherry blossoms bloomed They brought beauty to my heart. Tatsu-jo¹

Curator: Aviva Lev-Ari, PhD, RN

2 cherry-images

Image SOURCE: Google Images

https://www.google.com/search?q=cherry+blossom+tree&espv=2&biw=985&bih=526&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwjj1e_l34LMAhWMbz4KHfQ0DvIQsAQISg

A Personal Note

This article in the New York Times 4/9/2016 paid for and posted by The Embassy of Japan, cited, below, has reminds me of the Japan Cultural Center in Haifa, Israel neighboring the Dan Carmel Hotel on Mount Carmel in Haifa, Israel.

http://www.tmja.org.il/eng

My biography had intercepted Japanese Garden Designs and Japanese Ikebana flower arrangement, since 1965 to Present.

Tour with me the stops I named, below, while watching Japanese natural beauty or Japanese Man Made Nature in miniatures, including my visit to Japan, 5/2004.

In 1969, I took a course in Japanese Flower Arrangement, offered by a Japanese ikebana practitioner at Japan Cultural Center in Haifa, Israel. The Center had inside a bonsai collection and new Ikabana Arrangements were on display in the Building window infront of a black background behind the glass. I had great joy of looking at that window. My High School, Huggim was on Mount Carmel and I had many opportunities to visit this center, 1965-1968.

While an undergraduate student at HUJI, on Senior year a took a course on Japan during the Meiji Period and wrote a Paper (Seminarion Thesis) on Japanese Education System Reform in the late 19th Century under Professor Ben-Ami Shillony, HUJI.

Since 1978, I lived in California twice, and visited many times Japanese Gardens.

  • 9/1978 to 9/1990 in Palo Alto, CA while a PhD Student at University of California, Berkeley, 9/1978 t0 12/1983.

My son was born in San Francisco. 1981 was a year, I was in the city every month or twice a month, several times visiting the Japanese Tea Garden in the Golden Gate Park, Fan Francisco.

Japanese Tea Garden, the oldest public Japanese garden in the United States located inside Golden Gate Park in San Francisco, California. Tea Garden celebrated on Monday, April 4th, 2016 in horn or of Golden Gate Park’s 146th Birthday

http://japaneseteagardensf.com/

Japanese Cultural and Community Center of Northern California

http://www.jcccnc.org/

 

Moved to Boston in 8/1990 and I enjoy the Zen Garden at the Museum of Fine Arts.

MFA-SC24483_4x3

Dedicated in October 1988, Tenshin-en, or the “Garden of the Heart of Heaven,” is a contemplative Japanese garden. Named for the Museum’s curator of Chinese and Japanese Art, Kakuzō Okakura (known in Japan as Okakura Kakuzō and also as Okakura Tenshin), who worked at the MFA from 1904 until his death in 1913, Tenshin-en was designed as a viewing garden in the karesansui style by the late Professor Kinsaku Nakane of Kyoto.

http://www.mfa.org/collections/featured-galleries/japanese-garden-tenshin-en

Boston’s The Bonsai & Penjing Collection

The Larz Anderson Collection of Japanese Dwarfed Trees at the Arnold Arboretum was originally imported into the United States by the Honorable Larz Anderson in 1913, upon his return from serving as ambassador to Japan. In April 1937, Isabel Anderson donated the majority of her late husband’s bonsai collection (30 plants) to the Arnold Arboretum, along with the funds necessary to build a shade house for their display. The rest of the Anderson bonsai came to the Arboretum following Isabel’s death in 1949. Records of the Larz Anderson Bonsai Collection [pdf] documents the history and maintenance of this collection.

SEE 12 Bonsai Species

http://www.arboretum.harvard.edu/plants/featured-plants/bonsai/

 

  • 5/2002 – 9/2004 I lived in Monterey, CA while working for McGraw-Hill.

Japanese Garden, Monterey, CA

Monterey-images

https://www.google.com/search?q=Japanese+garden+Monterey,+CA&espv=2&biw=985&bih=526&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwj99c3ozYLMAhVKbj4KHSsJCfEQsAQIIg&dpr=1.25

My trip to Florida in 12/2000, involved a visit to Morikami Museum, Del Ray, FL

Morikami’s gardens, named Roji-en: Garden of the Drops of Dew, were designed to be a living exhibit complementing the museum. Here in Roji-en, designer Hoichi Kurisu sought to create a garden complex for the new millennium. Its six distinct gardens are inspired by, but are not replicas of, famous gardens of Japan. Kurisu has created a unique garden conceived and constructed in the spirit of the masters.

stone-lantern-150x150

woodruff-bridge-150x150

http://morikami.org/roji-en/

 

My trip with HLA to Vancouver, BC, Canada, 4/2002 – Nitobe Garden

Nitobe Memorial Garden, a traditional Japanese Tea and Stroll garden located at the University of British Columbia. Nitobe Garden is considered to be the one of the most authentic Japanese gardens in North America and among the top five Japanese gardens outside of Japan. Nitobe Garden includes a rare authentic Tea Garden with a ceremonial Tea House.

“I am in Japan,” said Akihito, Crown Prince (now Emperor) of Japan as he walked through UBC’s renowned Nitobe Memorial Garden. The exquisite work of art was created out of one hectare (two-and-a-half acres) of pristine forest by landscape architects and gardeners recommended by the Government of Japan.

The garden honours Inazo Nitobe (1862-1933) whose goal was “to become a bridge across the Pacific.” Among many other memorials to him is his portrait on the 5000 yen note.

http://botanicalgarden.ubc.ca/visit/nitobe-memorial-garden/

nitobe1download

Nitobe2images

Image SOURCE: Google Images

https://www.google.com/search?q=nitobe+garden+cherry+blossom&client=safari&hl=en-us&biw=985&bih=526&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwj3rOeNgIfMAhUJWz4KHV1nAvgQsAQIGw

My Trip with HLA to Ichimura Miami-Japan Garden 12/2001

In 1957, Mr. Kiyoshi Ichimura, Founder of Ricoh Corporation of Japan, attended a camera exhibition and show in the United States. On his way from Japan to the exhibition, he stopped in Miami. Looking east from his hotel room, he was stunned by the beauty of the city. He noticed one nearby area of land that appeared vacant and idle.

Mr. Ichimura remarked to the American gentleman standing next to him that it would be wonderful if hundreds of cherry trees could be planted there with a great number of standing lanterns interspersed among them. The American gentleman, who happened to be a Miami city commissioner, responded to the remark with a question, “Are you willing to donate them?” Mr. Ichimura answered without hesitation,”Yes, any time, if you wish.”

Soon after, Mr. Ichimura received a phone call from the Mayor of Miami inquiring about the seriousness of his remarks. The Mayor reportedly said, “We will accept your gift wholeheartedly; however, we will need some preparation time to be ready to accept such a generous gift.”

The following year, when Mr. Ichimura attended the camera show, he again stopped in Miami and took the opportunity to present to the City of Miami an intended list of gifts. Sadly, it was determined that the climate in Miami was unsuited for cherry trees and furthermore that cherry trees could possibly carry a bacteria that prohibited their importation.

http://friendsofjapanesegarden.com/history/

My Trip with my sister to Washing DC, 4/2002 and 4/2012

We took a boat tour on the Potomac River to see the Cherry blossom in 360 degrees

David Coleman Photography / Washington DC

http://images.havecamerawilltravel.com/#!/index/G0000XEn0haQW8qg

VIEW 50 IMAGES of Cherry Blossom in Washington, DC by David Coleman Photography

http://images.havecamerawilltravel.com/#!/index/G0000XEn0haQW8qg/I000059QjG9gSSBs

Cherry-Blossoms-Washington-DC-April-09-2013-11-513x250

http://cherryblossomwatch.com/

My trip with HLA to Japan, 5/2005, involved visits to Kyoto, Nara, Kobe and Osaka

Japanese Garden in Kyoto

Kyoto-download

Beautiful-Kyoto-Gardens

Image SOURCE: Google Images

https://www.google.com/search?q=japanese+garden+in+kyoto&espv=2&biw=985&bih=526&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwjx4cnH2ILMAhWFWj4KHbeTCP4Q7AkIJg

Japanese Garden in Kobe

Sorakuen

http://www.japan-guide.com/e/e3560.html

Japanese Garden in Nara

Isuien-4114_01

Cherry-4114_02

http://www.japan-guide.com/e/e4114.html

Japanese Garden in Osaka

Osaka-download

2Osaka-images

Image SOURCE: Google Images

https://www.google.com/search?q=Japanese+Garden+in+Osaka&espv=2&biw=985&bih=526&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwiou8HZ24LMAhWMMj4KHS-qCegQsAQIIg

My visit Saratoga, CA – Hakone Garden, 1/2015

One of the National Trust for Historic Preservation’s premier sites and 100 years old, Hakone is one of the oldest Japanese estate, retreat and gardens in the Western Hemisphere.  Hakone has also been on the National Register of Historic Places since 2013. 18 acres of magnificent beauty is nestled in the verdant hills of Saratoga overlooking Silicon Valley.

Floral designers from the three Ikebana Schools—Ikenobo, Sogetsu and Ohara—creating designs showcasing the design concepts of their particular school.

http://www.mfa.org/programs/special-event/celebrate-art-in-bloom-with-ikebana

National Cherry Blossom Festival 2016

The National Cherry Blossom Festival in Washington, DC

Every year in Washington, DC, the National Cherry Blossom Festival is held to welcome spring and celebrate the friendship between Japan and the US. All kinds of performances, events and activities are planned during the Festival’s three-week span. But you have to wonder, how did all of this get started?

The answer takes us back to 1912, the 45th year of the Meiji Emperor’s reign. That year the Mayor of Tokyo, Yukio Ozaki, gifted 3,000 cherry trees to Washington, DC as a symbol of the friendship between the two nations. Ms. Eliza Scidmore, the author of a travel journal who was deeply impressed by the beauty of the cherry blossoms at Mukoujima in Tokyo, had campaigned for years to have them brought to DC. Along with Dr. Joukichi Takamine, famous for his work on adrenaline and the enzyme taka-diastase and a long-time friend of America, she urged First Lady Helen Taft to have the trees planted along the Potomac. Now every year the public parks along the banks of the Potomac River in Washington are covered in gorgeous blooming trees, delighting the public who come to see them.

The first festival commemorating the gift from Japan and the friendship it represented was held in 1927. Now it has grown into the largest such celebration in America, welcoming more than 1.5 million visitors each year. The Opening Ceremony in particular, with its captivating performances from artists representing both Japan and the US, enjoys a high degree of popularity both locally and abroad in Japan. The National Cherry Blossom Festival Parade and the Sakura Matsuri – Japanese Street Festival, held together on the final day of the festival, also draw packed crowds.

Helpful links: National Cherry Blossom Festival | Sakura Matsuri – Japanese Street Festival

http://www.us.emb-japan.go.jp/jicc/events/ncbf2016.html

Celebrating a Treasured Friendship – New York Times 4/9/2016 article

The Gift of Cherry Blossoms: Honoring the Friendship of Two Nations (Paid Post by Embassy of Japan From The New York Times)

Explore the rich history behind this international festival, and find one near you.

http://paidpost.nytimes.com/embassy-of-japan/the-gift-of-cherry-blossoms-honoring-the-friendship-of-two-nations.html?emc=eta1

In 1912, Mayor Yukio Ozaki of Tokyo gave 3,000 cherry blossom trees to Washington, D.C., as symbols of friendship, forever changing the springtime vistas of the nation’s capital. Three years later, the United States reciprocated by sending dogwood saplings to Japan, deepening the ties between the two countries.

Beginning in the 1920s, the trees’ spectacular blooming inspired celebrations of international friendship and spring renewal, evolving into today’s city-wide, multi-week National Cherry Blossom Festival. Cared for by the National Park Service, the trees’ famously breathtaking, yet fleeting, display is found surrounding the Tidal Basin, lining the Potomac River and enhancing the Washington Monument grounds.

A vibrant expression of the bond between the U.S. and Japan, the National Cherry Blossom Festival is renowned as the “nation’s greatest springtime celebration,” according to festival President Diana Mayhew. “We’ll never forget the roots of where this all started … where these trees came from and the symbol of peace and friendship they represent.”

WATCH VIDEO

http://paidpost.nytimes.com/embassy-of-japan/the-gift-of-cherry-blossoms-honoring-the-friendship-of-two-nations.html?emc=eta1

Photos of the Cherry Blossom Festival in Washington DC by Ron Engle

PART 1Celebrating aTreasured Friendship

PART 2From Cherry Blossoms toJapanese Gardens

PART 3Nature Within a Garden

PART 4Nature Brought Home

PART 5Find a Garden orFestival Near You

http://paidpost.nytimes.com/embassy-of-japan/the-gift-of-cherry-blossoms-honoring-the-friendship-of-two-nations.html?emc=eta1

The National Bonsai & Penjing Museum at the U.S. National Arboretum in Washington, D.C., celebrating its 40th anniversary in 2016, has several works by Naka and other bonsai masters.

Japanese Gardens, Cherry Blossoms and Festivals

Enjoy these extraordinary expressions of nature’s beauty and cherish the connection with our nation’s longtime friend, Japan, at over 250 Japanese gardens in the U.S. Here are 30 of the most celebrated Japanese gardens and festivals throughout the country.

SEE MAP 

PART 5Find a Garden orFestival Near You

SOURCE

http://paidpost.nytimes.com/embassy-of-japan/the-gift-of-cherry-blossoms-honoring-the-friendship-of-two-nations.html?emc=eta1

 

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