During percutaneous coronary intervention (PCI), dislodgement of atherothrombotic material from coronary lesions can result in distal embolization, and may lead to increased major adverse cardiovascular events (MACE) and mortality. We sought to systematically review the comparative effectiveness of adjunctive devices to remove thrombi or protect against distal embolization in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI of native vessels.http://www.clinicaltrials.gov, abstracts from major cardiology meetings, TCTMD, and CardioSource Plus. Two investigators independently screened citations and extracted data from randomized controlled trials (RCTs) that compared the use of adjunctive devices plus PCI to PCI alone, evaluated patients with STEMI, enrolled a population with 95% of target lesion(s) in native vessels, and reported data on at least one pre-specified outcome. Quality was graded as good, fair or poor and the strength of evidence was rated as high, moderate, low or insufficient. Disagreement was resolved through consensus.We conducted a systematic literature search of Medline, the Cochrane Database, and Web of Science (January 1996-March 2011), 37 trials met inclusion criteria. At the maximal duration of follow-up, catheter aspiration devices plus PCI significantly decreased the risk of MACE by 27% compared to PCI alone. Catheter aspiration devices also significantly increased the achievement of ST-segment resolution by 49%, myocardial blush grade of 3 (MBG-3) by 39%, and thrombolysis in myocardial infarction (TIMI) 3 flow by 8%, while reducing the risk of distal embolization by 44%, no reflow by 48% and coronary dissection by 70% versus standard PCI alone. In a majority of trials, the use of catheter aspiration devices increased procedural time upon qualitative assessment.Distal filter embolic protection devices significantly increased the risk of target revascularization by 39% although the use of mechanical thrombectomy or embolic protection devices did not significantly impact other final health outcomes. Distal balloon or any embolic protection device increased the achievement of MBG-3 by 61% and 20% and TIMI3 flow by 11% and 6% but did not significantly impact other intermediate outcomes versus control. Upon qualitative analysis, all device categories, with exception of catheter aspiration devices, appear to significantly prolong procedure time compared to PCI alone while none appear to significantly impact ejection fraction. Many of the final health outcome and adverse event evaluations were underpowered and the safety of devices overall is unclear due to insufficient amounts of data.In patients with STEMI, for most devices, few RCTs evaluated final health outcomes over a long period of follow-up. Due to insufficient data, the safety of these devices is unclear. Over 650,000 deaths were attributed to coronary heart disease (CHD) in the United States in 2003 . CoronarPatients with no-reflow may have larger infarcts, more significant left ventricular systolic dysfunction, and an increased risk of major adverse cardiovascular events (MACE) or death. Numerous adjunctive devices have been developed to remove thrombi or protect against distal embolization during PCI . These dhttp://www.effectivehealthcare.ahrq.gov. The authors have no conflicts of interest.We developed and followed a standard protocol for all steps of this review, which underwent review by a panel of experts in the field as well as the public. The peer-reviewed final report details the methodology including the analytic framework, literature search strategy, and analysis plan as well as evidence tables and is available at We refined key questions in collaboration with a panel of technical experts which included cardiologists, internists, and representatives from managed-care organizations. The following key questions in patients with STEMI who are undergoing PCI of native vessels were defined:1. What are the comparative effects of adjunctive devices from different classes on intermediate  and final health outcomes ?2. How do the rate and type of harms  differ between device types when compared to PCI alone?http://www.effectivehealthcare.ahrq.gov, includes information and results of analyses specific to patients with non-ST-segment myocardial infarction (NSTEMI), unstable angina (UA), or mixed ACS , results from observational trials with over 500 patients, and information on results in various subpopulations.The final report of this comparative effectiveness review, available at http://www.tctmd.com, CardioSource Plus http://www.cardiosource.com, and http://ClinicalTrials.govhttp://www.clinicaltrials.gov web sites. We updated the literature search in March 2011 during the peer review period using the same search strategy.We conducted a computerized literature search of Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from January 1996- March 2010, without language restrictions. We restricted the search to 1996 and later to reflect contemporary practice. The complete search strategy is included in Additional File a priori criteria. RCTs of any size were eligible for inclusion if they: 1) compared the use of adjunctive devices plus PCI to PCI alone, 2) included patients with STEMI, 3) had ≤ 5% of the study population receiving PCI of saphenous veins, and (4) reported data on at least one pre-specified intermediate outcome, final health outcome, or harm. Given the known benefit of distal embolic protection devices in patients undergoing PCI of a saphenous vein graft, this review was restricted to a population with lesions primarily in native vessels.Two independent reviewers assessed studies for inclusion in a parallel manner using Two reviewers used a standardized data extraction tool to independently extract study data. Data extracted from each study included interventions, study design, inclusion and exclusion criteria, methodological quality criteria, study population, baseline patient characteristics, use of concurrent standard medical therapies, and pre-specified benefits and harms.Two reviewers independently assessed the validity and strength of evidence using recommendations in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews . We asseWe used a modified version of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the strength of evidence for each outcome of interest. Four required domains were evaluated- risk of bias, consistency, directness, and precision. We classified the strength of evidence for each outcome as high, moderate, low, or insufficient.2 statistic  and we used Egger's weighted regression statistic to assess for the presence of publication bias [We qualitatively examined data from all identified studies. Six device classes were considered and for each outcome, we conducted separate analyses of studies that compare each device class with control or two device classes to each other. Device classes included catheter aspiration, mechanical thrombectomy, distal filter embolic protection, distal balloon embolic protection, proximal balloon embolic protection, and embolic protection devices combined . We conducted meta-analyses when two or more RCTs that were adequate for data pooling were available for any outcome. For dichotomous outcomes, weighted averages are reported as relative risks (RR) and risk differences (RD) with associated 95 percent confidence intervals using a DerSimonian and Laird random-effects model . We usedion bias . We usedWe defined attainment of optimal myocardial reperfusion as a MBG-3 or TIMI-3 blood flow (or a MBG or TIMI blood flow of at least two in studies not reporting the other endpoint) and ST-segment resolution as 70 percent resolution in peak ST-segments (or at least 50 percent resolution in studies not reporting the other endpoint). We used results for ST-segment resolution at or close to 60 minutes post-PCI and never exceeding 90 minutes post-PCI. For final health outcomes, we defined the base-case analysis using the maximum duration of follow-up for which a final health outcome was reported.To assess the effect of heterogeneity  on the conclusions of our meta-analysis, we conducted subgroup and sensitivity analyses based on study quality  and duration of follow-up on the efficacy of adjunctive devices. Data at different follow-up times  were pooled in separate subgroup analyses.The University of Connecticut/Hartford Hospital Evidence-based Practice Center prepared this systematic review, with funding from the Agency of Healthcare Research and Quality. The funding source formulated draft research questions and provided the copyright release for this manuscript, but did not participate in the literature search, data collection or analysis, or interpretation of the results.We screened 1,091 abstracts and 438 full text articles  towards reducing mortality, myocardial infarction, and target revascularization versus PCI alone Table . Distal When we evaluated final health outcomes over several different time periods, we found several significant findings Table . CatheteThe use of catheter aspiration devices plus PCI significantly increased the achievement of STSR by 51%, MBG-3 by 61% and TIMI-3 flow by 8% while they significantly decreased the risk of no reflow by 52% and distal embolization by 56% versus PCI alone Table  to 49. TWe qualitatively evaluated ejection fraction for each device category versus standard PCI Table . Based oThe use of catheter aspiration devices plus PCI significantly decreased the risk of coronary dissection by 70% compared to PCI alone and no events occurred in the one trial evaluating coronary perforation Table  to 54. MCatheter aspiration devices plus PCI does not appear to prolong procedure time since a majority of trials  evaluating this outcome found no significant differences versus PCI alone Table . MechaniDetermining the balance of benefits to harms is difficult because many of the final health outcome and adverse event evaluations were underpowered and the safety of devices overall is unclear due to insufficient amounts of data. We do not know for certain whether the non-significant increases or decreases observed were due to a real effect or to chance.In the catheter aspiration trials, the risk of MACE and coronary dissection were significantly lower in the overall analyses and the good quality trial analyses. However, the risk of mortality, myocardial infarction, and target revascularization were not significantly impacted  and a non-significant increase in the risk of stroke was found. However, STSR, MBG-3, TIMI-3, no reflow, and distal embolization were favorably impacted by catheter aspiration devices compared to standard PCI. As such, more research is needed to truly determine the balance of benefits to harms but use of catheter aspiration devices looks promising.Mechanical thrombectomy device use did not result in any significant differences in the final health outcomes or coronary dissection and coronary perforation in the overall analyses and analyses limited to good quality trials. However, these devices significantly increased the time needed to conduct the PCI procedure in three trials. While the risk of myocardial infarction, target revascularization, mortality and MACE were not significantly different versus control, these findings may be misleading since many of the trials evaluating this procedure versus control had a shorter duration of follow-up. When we evaluated mortality and MACE in studies of 365 days or longer, there was no significant difference in mortality risk although there was a significant reduction in MACE, based on the results of a single trial. Unlike with catheter aspiration devices, there are no significant beneficial effects on intermediate health outcomes and while most are in the right direction of effect, the chance of achieving near normal (TIMI-3) blood flow was not significantly different versus control. As such, more research is needed to truly determine the balance of benefits to harms with mechanical thrombectomy devices.The use of embolic protection devices was based on a limited number of studies and one significant finding  on final health outcomes was seen in overall analyses and those limited to good quality trials. It was difficult to assess the impact on final health outcomes and intermediate outcomes for these devices. Distal balloon devices significantly increased the chance of achieving a MBG-3 or near normal (TIMI-3) blood flow but did not significantly impact the achievement of STSR, prevention of no reflow, or the risk of distal embolization. Distal filter devices did not significantly impact STSR, distal embolization, no reflow, attainment of near normal (TIMI-3) blood flow, or MBG. There was a paucity of trials available to evaluate adverse events with any of the embolic protection devices. The only significant finding was an increased time to perform a PCI procedure for all three types of embolic protection devices individually and when evaluated together versus control. As such, the balance of benefits to harms cannot be determined for these device classes.The use of thrombus removal and embolic protection devices hold promise in the adjunctive treatment of patients with STEMI undergoing primary PCI. However, to truly discern the role of these devices in contemporary practice, a number of important research questions need to be answered. In our analysis, we found that for many endpoints, non-significant increases or decreases were seen versus control, even when we evaluated compound endpoints, used the maximum duration of follow-up, and combined three different types of embolic protection devices together. All of these were strategies to enhance power to detect differences between groups but by and large, did not provide adequate power. Ultimately, the impact of using these devices on long-term final health outcomes versus control needs to be determined.Previous systematic reviews have attempted to address this topic. However, only four of 11 which were identified through our systematic literature search comprehensively included devices from all three device categories including catheter aspiration devices, mechanical thrombectomy, and embolic protection -51. AlbeBased on these research gaps we propose the following avenues for future research. We believe that additional multicenter, randomized, placebo-controlled trials should be conducted to determine the impact of adjunctive clot removal or embolic protection devices on final health outcomes using a long term follow-up versus PCI alone. At least two such trials are currently ongoing, Thrombus Aspiration in STEMI in Scandinavia (TASTE) and a Trial of Routine Aspiration Thrombectomy with PCI versus PCI alone in Patients with STEMI Undergoing Primary PCI (TOTAL) ,53. BothIn patients with STEMI, for most devices, few RCTs evaluated final health outcomes over a long period of follow-up. Due to insufficient data, the safety of these devices is unclear.ACS: acute coronary syndrome; CHD: coronary heart disease; HRQoL: health-related quality of life; MACE: major adverse cardiovascular event; MBG: myocardial blush grade; NSTEMI: non-ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; RCT: randomized controlled trial; RD: risk difference; RR: relative risk; STEMI: ST-segment elevation myocardial infarction; STSR: ST-segment resolution; TCT: transcatheter cardiovascular therapeutics; TIMI: time in myocardial infarction; UA: unstable angina.The authors declare that they have no competing interests.DMS, CMW, JK and CIC contributed to the conception of design, acquisition, analysis and interpretation of data, and drafted the manuscript. VT, JC, WTC, SSM, SL, and AA contributed to the acquisition and analysis of data and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/11/74/prepubLiterature search strategy. This file contains the literature search strategy used for this review.Click here for fileTable S1. Baseline study characteristics. This file contains an additional table with included trial baseline characteristics.Click here for fileImpact of catheter aspiration devices versus control on mortality using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on mortality using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on mortality using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on mortality using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on mortality using the maximal duration of followup in patients with ST- segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on mortality using the maximal duration of followup in patients with ST- segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on mortality using the maximal duration of followup versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on mortality using the maximal duration of followup versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on mortality using the maximal duration of followup in patients with ST- segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on mortality using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on myocardial infarction using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on occurrence of stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on occurrence of stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on stroke using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on target revascularization using maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on target revascularization using maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on target revascularization using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on MACE of maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on MACE of maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on MACE using the maximal duration of followup in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction Figure of the Impact of mechanical thrombectomy devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on ST-segment resolution in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on myocardial blush grade of 3 in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on TIMI- 3 blood flow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on TIMI- 3 blood flow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on TIMI- 3 blood flow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on TIMI- 3 blood flow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on TIMI-3 blood flow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices versus control on distal embolization in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on distal embolization in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on distal embolization in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal filter embolic protection devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal filter embolic protection devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices versus control on no reflow in patients with ST-segment elevation myocardial infarction Figure of the Impact of distal balloon embolic protection devices versus control on no reflow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined versus control on no reflow in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined versus control on no reflow in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices on coronary dissection versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices on coronary dissection versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of mechanical thrombectomy devices on coronary perforation versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of mechanical thrombectomy devices on coronary perforation versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of catheter aspiration devices on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of catheter aspiration devices on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of distal balloon embolic protection devices on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of distal balloon embolic protection devices on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for fileImpact of embolic protection devices combined on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. Figure of the Impact of embolic protection devices combined on side branch occlusion versus control in patients with ST-segment elevation myocardial infarction. The squares represent individual point estimates. The size of the square represents the weight given to each study in the meta-analysis. Horizontal lines through each square represent 95 percent confidence intervals. The diamond represents the combined results. The solid vertical line extending from 1 is the null value.Click here for file


Reperfusion no-reflow (R-NR), characterized by TIMI 0/1 flow grade, is a phenomenon that occurs in up to 20% of percutaneous coronary intervention cases for acute myocardial infarction (AMI). R-NR involves reduced myocardial tissue perfusion in the presence of a reperfused and patent epicardial coronary artery. This phenomenon is associated with worse patient outcome and increased mortality. Potential contributing factors of R-NR include the initial ischemic insult, injury as a result of reperfusion, and possibly distal coronary embolization (DCE) of thrombotic material. The objective of this study was to develop a novel large animal model to investigate the effects of DCE in the setting of ischemia-reperfusion using microthrombi derived from autologous porcine blood.3.0 T CMR was performed on 25-30kg female Yorkshire pigs to determine baseline values of cardiac function, as well as the myocardial perfusion territory at risk using direct intracoronary injection of dilute Gadolinium-DTPA. Pigs were then subjected to balloon occlusion mediated myocardial ischemia distal to the second diagonal branch of the left anterior descending coronary artery (LAD) for 60 minutes. Following reperfusion, intracoronary injection of sterile saline (n=4) or microthrombi particles to simulate DCE (n=7) was performed. Epicardial coronary blood flow was assessed at each stage using x-ray angiography. At 72 hours following ischemia-reperfusion, CMR was used to assess changes in cardiac function, extent of edema/hemorrhage using T2/T2* relaxation times, evaluate infarct size, and to determine the presence/absence of microvascular obstruction (MVO). Myocardial tissue samples were subsequently collected for biochemical and histological analysis.Administration of 5-10 mg of microthrombi following 60 minute ischemia was sufficient to create no-reflow conditions following ischemia in all seven pigs. Early gadolinium enhancement imaging at 72 hours post-ischemia revealed the presence of MVO in 6 of 7 pigs which received microthrombi. MVO was not visible in 3 out of 4 control pigs administered saline following ischemia-reperfusion. Volumetric late-gadolinium enhancement images were used to evaluate infarct size. 11.7% of total LV volume (38.8% of perfusion territory) was infarcted for control, saline administered pigs. Pigs that received microthrombi had an infarct size of 12.9% of total LV volume (43.2% of perfusion territory). Global cardiac functional parameters did not reveal significant changes compared to baseline. Regional alterations in wall thickness/wall motion in addition to T2/T2* relaxation times were observed. Quantitative analyses of these parameters are in progress.Our porcine model is the first to combine myocardial ischemia with distal coronary embolization to more closely replicate the human condition. Our preliminary results suggest that DCE is capable of inducing no-reflow which results in microvascular obstruction as determined by MRI.Heart and Stroke Foundation of Ontario,Canadian Institutes of Health Research


It is well known that the natural history of chronic heart failure (CHF),regardless of age and aetiology,is characterized by progressive cardiac dysfunction refractory to conventional cardiokinetic, diuretic and peripheral vasodilator therapy. Several previous studies, both in animals and humans, showed that the key pathogenetic element of CHF negative clinical evolution is constituted by myocardial remodeling. This is a complex pathologic process of ultrastructural rearrangement of the heart induced by various neuro-humoral factors released by cardiac fibrocells in response to biomechanical stress connected to chronic haemodynamic overload. Typical features of myocardial remodeling are represented by cardiomyocytes hypertrophy and apoptosis, extracellular matrix alterations, mesenchymal fibrotic and phlogistic processes and by cardiac gene expression modifications with fetal genetic program reactivation. In the last years, increasing knowledge of subtle molecular and cellular mechanisms involved in myocardial remodeling has led to the discovery of some new potential therapeutic targets capable of inducing its regression. In this paper our attention is focused on the possible use of antiapoptotic and antifibrotic agents, and on the fascinating perspectives offered by the development of myocardial gene therapy and, in particular, by myocardial regenerative therapy. Treatment of heart failure has been long based on three main drugs to augment contractile force and lighten the heart’s workload, i.e. cardiokinetics to correct ventricular contractile deficit, diuretics to eliminate hydric-saline retention and vasodilators to reduce increased systemic resistances caused by peripheral vasoconstriction. Hydric-saline retention and vasoconstriction result from the release of adrenergic amines, angiotensin and aldosterone in circulation due to the reflex activation of adrenergic and renin-angiotensin systems triggered off by the drop of intraaortic pressure determined by systolic output reduction ,2. HowevIn the chronic form of heart failure, whether idiopathic or secondary to various causes  and generally linked to dilatative cardiomyopathies in childhood and adolescence, the therapeutic effectiveness of the above mentioned drugs tends to fade progressively over time. This may be because neuro-hormonal response linked to ventricular contractile deficiency can be overenhanced and thus severely damage heart function. In fact, while downregulation of adrenergic receptors resulting from the presence of excessive circulating amines inhibits adequate contractile response to adrenergic stimuli, increment of hydric-saline retention and intense peripheral vasoconstriction increase pre and after- load disproportionately. These effects result in more precarious heart performance giving rise to a vicious circle with progressive myocardial dysfunction that becomes more and more refractory to conventional treatment ,4 Figur. MoleculFurthermore, the same neuro-hormonal response can also be expressed to a greater degree inside the cardiac muscle and includes, together with catecholamines, angiotensin and aldosterone, other molecules such as endothelin, various proinflammatory cytokines  and some myocytic and vascular growth factors. These substances are released by cardiomyocytes after their mechano- receptors stimulation by biomechanical stress linked to chronic pressure and volume hemodynamic overload .Numerous experimental studies have shown that the humoral factors secreted by mechanically stressed cardiomyocytes activate a vast network of intra and intercellular transduction signals. Acting in autocrine and paracrine fashion in the same cardiomyocytes and in the surrounding tissues, they are able to alter myocardial ultrastructure and determine cardiac fibrocells hypertrophy and/or apoptosis, mesenchymal fibrotic and inflammatory processes and induce modifications in cardiac gene expression -11. ThisOne of the salient points in myocardial remodeling is altered cardiac gene expression, i.e. reactivation of fetal cardiac genetic program that can manifest with re-expression of genes that are hyperactive during the fetal period, including the gene of β-myosin (protein at low ATPasic activity poorly efficient in contractile function), some proapoptotic genes, and the gene of α subunit of Na,K dependent ATPase (an enzymatic variant having poor membrane stabilizing capacity). It may also involve inhibition of genes that are hyperactive in the adult heart, such as the genes of the sarcotubular ATPase , of β-adrenergic receptors , and of lipid β-oxidation (the main source of energy for the myocardium whose inhibition turns cardiac energetic metabolism into glycolysis that is poorly efficient for the heart) . In receTherefore, remodeling related processes determine marked changes in myocardium phenotype that make it functionally more precarious. These changes include anomalies involving important molecules regulating systolic and diastolic function , cytoskeletal proteins and extracellular matrix composition. In the cytoskeleton, enhanced protein filament expression and increased microtubular network density can lead to sarcomere disorganization, while in extracellular matrix, fibroblastic hyperplasia and augmented collagen synthesis with production of rigid type 1 collagen fibrils can reduce ventricular compliance .Instead of representing a useful compensatory event, in the long run also myocardial hypertrophy triggered off by chronic hemodynamic overload may damage the heart. Increased ventricular wall thickness initially reduces parietal stress (and hence oxygen requirement) and increases heart contractility. However, the compensatory effect is markedly curbed by subsequent re-expression of pro-apoptotic embryo-fetal genes and by fibroblastic hyperplasia with increased collagen synthesis, caused by the same biochemical mediators determining hypertrophy. Loss of contractile tissue due to cardiomyocytes apoptosis and mesenchymal fibrosis determined by increased collagen synthesis makes the heart dilate and stiffen, causing systolic and diastolic dysfunction  Figure . Thus, tThe recent advances achieved in the knowledge of molecular pathogenetic mechanisms of CHF have paved the way for new therapeutic approaches aimed at reversing myocardial remodeling and combating apoptotic and fibrotic processes responsible, respectively, for cardiomyocytes loss and myocardial wall rigidity, and thus jeopardizing global heart function.This strategy represents the first approach to antiremodeling treatment and used antagonists of the various humoral factors(see above) released by cardiomyocytes and involved in myocardial remodeling : i.e. ACE-inhibitors and sartanics for angiotensin; spironolactone and natriuretic peptides for aldosterone; β- blockers for adrenergic amines; direct antagonists (bosentan) for endothelin; monoclonal antibodies and soluble fusion receptors for cytokines ,24. The The increasing knowledge of the biochemical signals activated during myocardial remodeling have recently focused scientists’ attention on agents that can directly reverse the damaging apoptotic and fibrotic processes that impair heart function ,34.Concerning apoptosis, in various experimental animal models of CHF, apoptosis was hindered by substances that stimulate cardiomyocytes survival or inhibit death signals. Some potential therapeutic agents are cardiotrophin, a non inflammatory cytokine capable of activating GP-130-LIF protein and interrupting proapoptotic signals ,35; tetrAs regards antifibrotic treatment, preclinical studies (in murine models) have frequently shown that fibrosis can be curbed by various substances, such as inhibitors of TGF-β, a growth hormone that stimulates myofibroblasts collagen synthesis  and toraAlongside these measures targeting apoptotic and fibrotic processes, the most noteworthy perspectives in the treatment of CHF are those connected to the development of myocardial gene therapy and myocardial regeneration therapy.In the field of cardiovascular research the potential of gene therapy has been mostly explored in several models of inherited monogenic cardiac diseases. Recent insights concerning the molecular mechanisms and the identification of numerous genes and relative coded proteins involved in the pathogenesis of various acquired heart diseases have extended its application to heart failure.Myocardial gene therapy consists of an intramyocardial transfer of specific genes for some molecular targets involved in myocardial remodeling through viral (mainly adenovirus) or non viral vectors (plasmids or oligonucleotids). Extensive preclinical studies have shown that this therapeutic approach is able to modulate calcium homeostasis in cardiac myocytes, manipulate adrenergic receptors related biochemical signals and increase cardiomyocytes resistance to apoptosis. The results of these studies foresee the potential of a “molecular ventricular assistance” in the failing heart .Over the last few years, recent advances in myocardial gene therapy include improved vectors provided with greater trophism for myocardial cells and more efficient delivery methods, and have paved the way for translating experimental observations into therapeutic strategies in humans ,50. The Whether also the results of these studies confirm the clinical efficacy and safety of the treatment and other molecular targets  susceptible to gene manipulation will be successfully explored  in the nin vitro. The majority of these fascinating experimental researches have been carried out in acute and chronic ischemic cardiovascular pathologies and have mainly utilized bone marrow-derived mesenchymal stem cells that, together with embryonic-derived stem cells (rejected as they may determine teratomas), possess major cardiogenic potential [in vitro cultured RCSCs is able to promote myocardial and vascular tissue regeneration [in vitro and in vivo studies have revealed that because of their marked sensitivity to oxidative stress, these stem cells are particularly damaged by anthracycline, a well known producer of free radicals, and die more rapidly than mature cardiomyocytes. Furthermore, the ones that manage to survive malfunction in mature cardiac cells differentiation processes. Hence, in anthracycline-induced cardiomyopathy, massive RCSCs destruction damages physiological cardiomyocytes turnover and regeneration, leads to accumulation of ageing myocytes  in the heart, and, at the same time, prevents the onset of repair processes of myocardial damage caused by apoptosis and fibrosis [in vitro expanded RCSCs in rats with anthracycline-induced cardiomyopathy not only generated new cardiomyocytes and repopulated the heart with contractile elements, but also replaced fibrotic areas leading to structural and functional restoration of damaged myocardium [in vitro prior to anthracycline treatment, will represent a key therapeutic tool to prevent or treat severe heart dysfunction in patients with anthracycline-induced cardiomyopathy. In other forms of CHF where the RCSCs reserve pool is presumably not as severely impaired as in anthracyclinic cardiomyopathy, another emerging type of regenerative therapy could be intramyocardial delivery of trophic substances (various growth factors and non inflammatory cytokines) capable of stimulating cardiac stem cell proliferation and differentiation in situ[in vitro cultures and subsequent transplant. According to diverse experimental studies, such therapy exploits the fact that RCSCs possess specific receptors for these trophic substances and, once activated, not only proliferate and differentiate in myocardial and endothelial cells, but they also acquire the capacity to secrete trophic factors [in situ, but recent studies in animals with acute and chronic cardiac ischemic lesions have also identified some synthetic molecules, for example hyaluronan mixed esters of butyric and retinoic acid, affording myocardial repair [Myocardial regenerative therapy has been adopted to replace the loss of cardiomyocytes and repair damaged myocardial tissue. This therapy is based on myocardial transplantation of stem cells derived from embryos, muscle, endothelium, bone marrow, etc. capable of differentiating into myocardial and endothelial cells and vascular myocytes under special conditions otential . Howeverotential ,57 and motential . Neverthotential . Studiesneration . The utifibrosis  ”, “Therapeutic strategies to reverse myocardial remodeling “. Both authors read and approved the final manuscript.


Cardiac phenotypes, such as left ventricular (LV) mass, demonstrate high heritability although most genes associated with these complex traits remain unidentified. Genome-wide association studies (GWAS) have relied on conventional 2D cardiovascular magnetic resonance (CMR) as the gold-standard for phenotyping. However this technique is insensitive to the regional variations in wall thickness which are often associated with left ventricular hypertrophy and require large cohorts to reach significance. Here we test whether automated cardiac phenotyping using high spatial resolution CMR atlases can achieve improved precision for mapping wall thickness in healthy populations and whether smaller sample sizes are required compared to conventional methods.LV short-axis cine images were acquired in 138 healthy volunteers using standard 2D imaging and 3D high spatial resolution CMR. A multi-atlas technique was used to segment and co-register each image. The agreement between methods for end-diastolic volume and mass was made using Bland-Altman analysis in 20 subjects. The 3D and 2D segmentations of the LV were compared to manual labeling by the proportion of concordant voxels (Dice coefficient) and the distances separating corresponding points. Parametric and nonparametric data were analysed with paired t-tests and Wilcoxon signed-rank test respectively. Voxelwise power calculations used the interstudy variances of wall thickness.The 3D volumetric measurements showed no bias compared to 2D imaging. The segmented 3D images were more accurate than 2D images for defining the epicardium  and endocardium . The 3D technique resulted in significant differences in wall thickness assessment at the base, septum and apex of the LV compared to 2D (P < 0.001). Fewer subjects were required for 3D imaging to detect a 1 mm difference in wall thickness .High spatial resolution CMR with automated phenotyping provides greater power for mapping wall thickness than conventional 2D imaging and enables a reduction in the sample size required for studies of environmental and genetic determinants of LV wall thickness. The structure of the human heart is highly heritable and inflStandard 2D cine CMR comprises a stack of 8 mm sections with 2 mm gaps in the LV short axis plane which are acquired over several breath-holds. Three dThe primary purpose of this study was to evaluate the feasibility and accuracy of high spatial resolution3D cine imaging for phenotypic analysis of the LV; and secondarily to determine if this would enable a reduction in the sample size required for population-based research of myocardial hypertrophy.The study was supported by the Medical Research Council, UK, the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London, UK, and a British Heart Foundation, UK, project grant (PG/12/27/29489) and special grant (SP/10/10/28431). The authors had control of the data and information submitted for publication.This single-center prospective study was approved by the Hospital’s research ethics committee and all participants gave written informed consent. In total 138 adult volunteers  were recruited via advertisement for a sub-study of the UK 1000 Cardiac Phenomes project. We excluded participants at screening that had known cardiovascular disease or were being treated for hypertension, diabetes or hypercholesterolemia. Female subjects were excluded if they were pregnant or breastfeeding but were eligible if they took oral contraceptives. Standard published safety contraindications to MR imaging were applied. Twenty CMR was performed on a 1.5T Philips Achieva system . The maximum gradient strength was 33 mT/m and the maximum slew rate 160 mT/m/ms. A 32 element cardiac phased-array coil was used for signal reception. Scout images were obtained and used to plan 2D cine balanced steady-state free precession (b-SSFP) images in the left ventricular short axis (LVSA) plane from base to apex using the following parameters: repetition time msec/echo time msec, 3.0/1.5; flip angle, 60°; bandwidth, 1250 Hz/pixel; acquired pixel size, 2.0 × 2.2 mm; section thickness 8 mm with a 2 mm gap; reconstructed voxel size, 1.2 × 1.2 × 8 mm; number of sections, 10 – 12; cardiac phases, 30. A single breath-hold 3D LVSA b-SSFP sequence was acquired in the same orientation using the following parameters: 3.0/1.5; flip angle, 50°; bandwidth, 1250 Hz/pixel; pixel size 2.0 × 2.0 mm; section thickness, 2 mm overlapping; reconstructed voxel size, 1.2 × 1.2 × 2 mm; number of sections, 50 – 60; cardiac phases, 20; sensitivity encoding (SENSE) factor 2.0 anterior-posterior and 2.0 right-left direction.http://www.itk.org), and here we use p = 0.9. In order to conservatively account for the multiple comparisons in considering all P points independently, we use the Bonferroni adjusted significance level of α/P instead of simply α. Then f = 35.3892.where is 1 – γ. Here, αN = 20 control subjects at the two time-points; 2D segmentations denotedi =1,…,N and j = 1,…,P. For the 2D and 3D segmentations, the differences in wall thickness between time-points at each point across the myocardium are given byTwo myocardium images were obtained for each of P points of the 2D and 3D segmentations are computed and denotedδ = 1 at point j with f = 35.3892 (α = 0.05/16386 and p = 0.9) for the 2D and 3D segmentations can then be obtained viaThe variance of the differences at each of the respectively. The percentage decrease in sample size in using a 3D segmentation over a 2D segmentation can be computed at each point asThe authors declare that they have no competing interests.AdeM participated in the creation of the cardiac atlases, data analysis and drafted the manuscript. TJWD participated in the creation of the cardiac atlases and data analysis. WS and DR developed the co-registration and image analysis methods. CM and GM contributed to the statistical analysis of the data. GD scanned the patients and assisted in sequence development. TD recruited the subjects and collected anthrompometric data. NGK contributed to the manual data analysis. SAC and DPO’ Rconceived the research programme and coordinated this study. DPO’R participated in the drafting of the manuscript. All authors read and approved the final manuscript.


Pulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.A systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.Clinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation  is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation  is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation  is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation  is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation  is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation  is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation  is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.This systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed. Pulmonary vascular dysfunction is a broad term and may be central to several disease processes in the intensive care unit (ICU). Components include pulmonary endothelial dysfunction, altered lung microvascular permeability, vasoactive mediator imbalance, abnormal hypoxic vasoconstriction, pulmonary metabolic failure, microvascular thrombosis, and later, vascular remodelling -3. The r-5 (3 Wood units) , ,43, 4,43In addition, perfusion of the right coronary artery is usually dependent on a pressure gradient between the aorta and the right ventricle, which, in the setting of increased RV afterload and decreased coronary blood flow, may lead to RV ischemia , with fuThe gold standard for the diagnosis and management of PH and RV dysfunction in the ICU setting is considered by some to be through pulmonary artery catheterization (PAC), even though most of the information can be obtained noninvasively by echocardiography: the requirement for PAC in this population remains controversial. It must, however, be acknowledged that it provides the only direct continuous measurement of right-sided pressures and direct measurement of RV afterload, whereby, through measurement of cardiac output, pulmonary pressures and the pulmonary artery occlusion pressure , the PVR can be calculated Figure . OverallThe diagnosis and management of acute pulmonary embolism (PE) warrants a specific mention, as it is a relatively common cause of acute RV failure in the ICU . AvailabThe management of PH and RV dysfunction in the ICU is challenging. No agreed algorithms exist, although treatment should aim to prevent pulmonary hypertensive crises and acute cor pulmonale . These cWe performed a systematic review of the literature over the period from 1980 to 2010, by using set search terms, and the electronic database of the US National Library of Medicine and National Institute of Health (PubMed). After initial identification, abstracts were reviewed for relevance, and appropriate studies were included in the review. Reference lists of relevant articles were hand-searched for further studies and reports. The search was limited to publications in English. Studies were deemed suitable for inclusion according to the criteria listed and where the patient population and study design was defined; and the outcomes were limited to those depending on the specific GRADE question , and management involves fluid removal , perfusion of the right coronary artery usually occurs throughout the cardiac cycle, dominating in systole. It is understood that, as PVR approaches SVR, coronary perfusion will decrease, and if PVR exceeds SVR, coronary filling will occur only in diastole. By augmenting aortic root pressure by using vasopressors in the setting of increased RV afterload, RV ischemia can therefore be reversed . VasopreThese include the catecholaminergic pressor, norepinephrine, and the noncatecholaminergic pressor phenylephrine. Their complex effects on the pulmonary circulation depend on the dose-related relative α- and β-adrenoreceptor stimulation as well as the degree and nature of RV dysfunction ,100. AllNorepinephrine (NE) exerts its systemic vasopressor effects through α-1 agonism . ActivatPhenylephrine (PHE) is a direct α-agonist. Its use improves right coronary perfusion in RV failure  without Based on mostly low-quality evidence  causes systemic vasoconstriction via the vasopressinergic (V1) receptor. Experimental studies have revealed vasodilating properties at low doses that include pulmonary vasodilatation [1 receptors [Arginine latation  through eceptors ,114. Thieceptors ,115,116.eceptors -119, in eceptors ,120-124,eceptors ,126 and eceptors ,127,128.AVP leads to a diuretic effect in vasodilatory shock , reducesBased on mostly low-quality evidence  III inhibitors and levosimendan.Several types of PDE are recognized: PDEIII usually deactivates intracellular cyclic adenosine monophosphate (cAMP), and PDE3 inhibitors therefore increase cAMP and augment myocardial contractility while dilating the vasculature -158. TheNebulized milrinone is increasingly used to manage PH crises in several settings -179. Thr2 [Levosimendan sensitizes troponin-C to calcium and selectively inhibits PDE III, improving diastolic function and myocardial contractility without increasing oxygen consumption -183. It 2 .Based on low-moderate-quality evidence  after mitral valve replacement surgery results in easier weaning from cardiopulmonary bypass and shorter ICU stays [Inhaled nitric oxide (NO) is a potent pulmonary vasodilator with a short half-life due to rapid inactivation by hemoglobin. This minimizes systemic vasodilatation, although it necessitates continuous delivery into the ventilator circuit . NO seleCU stays ,240.NO has been shown to reduce PVR and improve CO in several studies in patients with acute RV failure due to ARDS ,241-246 NO provides synergistic pulmonary vasodilatation with intravenous prostacyclin , inhaled2  and its analogues, (iloprost) and prostaglandin-E1 . An important difference between their formulations is their resulting half-life : Increased RV afterload, reduced venous return, and acute RV dysfunction may result [Important variables that may reduce pulmonary blood flow during ventilation include hypoxia, hypercapnia, and compression of the pulmonary vasculature at the extremes of lung volumes Figure . Acute hy result . Both atplat reduces the incidence of RV failure [plat and pCO2 sufficiently to improve acute RV failure [Before the era of protective ventilatory strategies in ARDS, the incidence of acute RV failure was 60%  and has  failure . Prone v failure . In ARDS failure , and RV  failure . In chil failure ,338.Mechanical support for the RV may be appropriate in reversible settings or as a bridge to definitive treatment. RV-assist devices (RVADs) may be used in primary RV dysfunction  and haveBased on mostly very-low-quality evidence, the following WEAK recommendation is made: Mechanical therapies including ECMO and IABP may have a role as rescue therapies in reversible pulmonary vascular dysfunction or while awaiting definitive treatment.Pulmonary vascular and right ventricular dysfunction may complicate many ICU illnesses: the diagnosis may be difficult, and the acute management, challenging. Their presence is associated with a worse outcome. This review highlights that some recommendations can be made, despite limitations of the GRADE analysis. However, we do consider that "weak GRADE recommendations" could be interpreted as "management suggestions" and treated with appropriate caution. A further limitation is that several pathologies have been grouped together as one syndrome, although this relates to both the rarity of the syndrome and the lack of high-quality evidence: further research is desperately needed. In particular, only then will we learn whether PAH-targeted therapy such as use of PDE5 inhibitors or endothelin-receptor antagonists, so effective in idiopathic PAH, have a role in the ICU setting.• Pulmonary hypertension (PH) and associated right ventricular (RV) failure are associated with worse outcomes in critical care, and because of nonspecific presenting symptoms and signs, may be difficult to recognize: echocardiography is a very useful initial test, and invasive monitoring may be helpful in some cases for more continuous monitoring and accurate measurement of pulmonary vascular resistance.• Volume loading of the right ventricle may worsen its performance: all fluid challenges should be closely monitored.• It is essential to maintain adequate aortic root pressure to prevent the onset of RV ischemia. Vasopressors are useful in this setting, including low-dose norepinephrine as a first-line agent. Low-dose vasopressin may also be useful in some resistant cases but has adverse myocardial effects at higher doses. Potentially useful inotropes in RV failure include dobutamine and those with additional pulmonary vasodilating effects, including PDE III inhibitors, although co-administration with pressors is often necessary. The effects of any vasoactive drug may be unpredictable in an individual and require close clinical observation of circulatory performance, potentially assisted by echocardiography.• Pulmonary vasodilators are useful to reduce RV afterload in several ICU settings, including PH and RV failure after cardiac surgery. Systemic administration may worsen systemic hemodynamics and oxygenation because of ventilation-perfusion mismatching.• The use of mechanical therapies to manage acute PH and enhance RV performance is expanding, although with evidence currently limited to case series, and may be useful in experienced centers to ameliorate RV failure while awaiting definitive therapy.1: prostaglandin E1; PH: pulmonary hypertension; PHE: phenylephrine; PVR: pulmonary vascular resistance; RV: right ventricle; RVEF: right ventricular ejection fraction; RVF: right ventricular failure; SvO2: mixed venous oxygen saturation; SVR: systemic vascular resistance; TEE: transesophageal echocardiography; TR: tricuspid regurgitation; V/Q mismatch: ventilation/perfusion mismatch.ACP: acute cor pulmonale; ARDS: acute respiratory distress syndrome; AVP: arginine vasopressin; cAMP: cyclic adenosine 3',5'-cyclic monophosphate; cGMP: cyclic guanosine 3',5'-cyclic monophosphate; CI: cardiac index; CO: cardiac output; COPD: chronic obstructive pulmonary disease; CPB: cardiopulmonary bypass; CVP: central venous pressure; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; IABP: intraaortic balloon pump; LV: left ventricle; MVR: mitral valve replacement; NE: norepinephrine; NO: nitric oxide; PAC: pulmonary artery catheter; PAH: pulmonary arterial hypertension; PAOP: pulmonary arterial occlusion pressure; PDE: phosphodiesterase; PE: pulmonary embolism; PGELCP has received honoraria from Encysive Pharmaceuticals. SJW has received honoraria from Actelion Pharmaceuticals. SJB has received support for clinical trials from Pfizer, Astra Zeneca, and Baxter Healthcare.LCP and SJB conceived of the review and participated in its design. LCP and SJW carried out the literature search and drafted the initial manuscript. All authors read and approved the final manuscript.Population, Intervention, Comparison and Outcome (PICO) evidence tables. This file contains structured detail for all studies included in the systematic review. According to GRADE method guidelines, a series of eight study questions was devised to approach the questions posed by the systematic literature review. The PICO table then describes each study according to the study type, the population studied, the intervention applied, the nature of the comparison or control group, and the studied outcome of interest appropriate to the study question. The final column grades the evidence according to the GRADE evidence level as very low-, low-, moderate-, or high-level evidence [evidence ,81.Click here for file


The clinical syndrome of heart failure is the final pathway for a myriad of diseases that affect the heart, and is a leading and growing cause of morbidity and mortality worldwide. Evidence-based guidelines have provided clinicians with valuable data for better applying diagnostic and therapeutic tools, particularly the overwhelming new imaging technology and other, often expensive, therapies and devices, in heart failure patients. In the Middle East, progress has recently been made with the development of regional and multi-centre registries to evaluate the quality of care for patients with heart failure. A new heart function clinic recently began operation and has clearly resulted in a reduced readmission rate for heart failure patients. Many Middle Eastern countries have observed increases in the prevalence of the risk factors for the development of heart failure, including diabetes mellitus, obesity, and hypertension, with heart failure in the Middle Eastern population developing earlier than it is in their Western counterparts by at least 10 years. The earlier onset of disease is the result of the earlier onset of coronary artery disease, highlighting the need for Middle Eastern countries to establish prevention programs across all age groups. The health systems across the Middle East need to be modified in order to provide improved evidence-based medical care. Existing registries also need to be expanded to include long-term survey data, and additional funding for heart failure research is warranted. Heart failure (HF) may be defined as an abnormality in cardiac structure or function that leads to the failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures) . Clinica-2% of the adult population, with the prevalence rising to ≥10% among persons 70 years of age or older [In developed countries, the prevalence of HF is approximately 1%or older . In Euroor older , 6. The or older .Comprehensive studies evaluating the prevalence of HF, and associated mortality, are lacking in the Middle East; however, scattered data from individual regions are available, including a recent Saudi prospective registry trial that reported the overall 30-day mortality rate for 1090 acute HF patients to be 7.5% [-15 years, there have been important advances in the diagnosis and treatment of HF. These have included diagnostic advances, particularly in the field of diagnostic imaging, and in the recognition of new diagnostic indicators, such as serum natriuretic peptides. The host of therapeutic advances over this period has included new drugs, such as the aldosterone antagonists that function as selective sinus node blockers, and implantable devices which have helped to delay the deaths of HF patients. In addition, the development of heart function clinics has led to reduced patient readmissions. The studies of heart failure in Middle East are scanty and there are no comprehensive long term studies, however through this paper the available data will be reviewed in terms of prevalence, aetiology, pathophysiology, diagnosis, treatment and prognosis of HF in the Middle East.Over the last 10-D (Table 1).The New York Heart Association (NYHA) classification is traditionally used to describe the clinical symptoms of HF patients, without any consideration of the aetiology or physiology of HF. The classification system is divided into 4 classes, Class I to Class IV, and is bidirectional, i.e., patients in Class I may progress to Class IV, and, with treatment, Class IV patients may improve to Class I or II. The American Heart Association guidelines, published in 2001  addresseCardiologists have borrowed a concept from cancer pathophysiology that involves the use of cytotoxic drugs to prevent stent re-stenosis by inhibiting intimal proliferation, following the use of bare metal stents for the treatment of coronary artery disease. As a result, some causes of HF are now preventable, but require screening similar to that for breast and prostate cancers . Thus, a-46% (Table 2) [The emergence of different echocardiographic modalities allow further classification of HF, in the form of Heart Failure with Reduced Ejection Fraction (HF-REF) and Heart Failure with Preserved Ejection Fraction (HF-PEF). HF-PEF is defined as an ejection fraction ranging from 40 to ≤50% , 13. TheTable 2) , 13-17.3) [The diagnosis of HF-PEF is more difficult than the diagnosis of HF-REF because it is largely one of exclusion, i.e., potential non-cardiac causes of the patient’s symptoms (such as anaemia or chronic lung disease) must first be excluded (Table 3) .The differences in the prevalence of diastolic HF, or HF-PEF, in Middle Eastern studies is probably related to bias in the selection of cohorts or to the lack of accurate use of echocardiographic diagnostic criteria for diastolic dysfunction. Comparing the prevalence of HF-PEF in the Middle East to data from the USA, a similar incidence of HF-PEF is revealed (approximately 33% of HF patients) . HoweverWorldwide, the most common causes of HF include ischemic heart disease (IHD), hypertensive heart disease, idiopathic cardiomyopathy, and, to a lesser extent, valvular heart disease. In several Middle Eastern countries, like Oman, Saudi Arabia, and Yemen, around 52% of HF cases are secondary to IHD , 14, 15;In the Western literature, coronary heart disease (CHD) is by far the most common cause of myocardial disease, being the initiating cause in 70% of patients with HF ; valve d-25% [The prevalence of risk factors for HF is increasing. For example, 26% of the Saudi population is affected by hypertension  and appr-25% . The pre-25% , which i-25% . Age als-25% , 25-31. -25% -34.The diagnosis of HF can be difficult, especially in the early stages. Although symptoms lead patients to seek medical attention, many of the symptoms of HF are non-specific and do not, therefore, help to discriminate between HF and other problems. Symptoms that are more specific  are less common, especially in patients with milder symptoms -39, makiECGs and echocardiograms are 2 of the most important diagnostic tests, and both are commonly available in the Middle East. Echocardiograms were performed in 98% of the recently conducted studies like, Heart Function Assessment Registry Trial in Saudi Arabia (HEARTS) . EchocarOverwhelming evidence, gathered from clinical trials, has proved the prognostic advantages of treating HF patients with drugs like angiotensin-converting enzymes inhibitors (ACEI), angiotensin receptor blockers (ARBS), beta-blockers, and aldosterone antagonists. A variety of clinical practice guidelines emphasize the importance of these drugs, but a considerable proportion of HF patients do not receive these medications. In a European heart survey, published in 2006 , 80% of In the Middle East, the use of these important medications is variable. In the HEARTS study, ACEI/ARBS use was 86%, beta-blocker use was 95%, and aldosterone antagonist use was 53%. In Assir , 43 (souBoth cardiac resynchronization therapy (CRT) and intracardiac defibrillation (ICD) were under-used in Saudi Arabia, based upon the HEARTS report; a history of ICD and CRT insertion were documented in 29% and 8% of the patients respectively. New implant rates for ICD of 5% and CRT of 1.7% were reported.-2010), with the overall mortality rate declining from 8.4% to 4.8% over the study period. This is consistent with the findings from both the Olmsted County (USA) Study (1979-2000) [-2000) [In Europe, 50% of HF patients died within 4 years of diagnosis , with 1379-2000)  and the  [-2000) . Middle Eastern countries need to develop preventive programs to combat HF due to the increased prevalence of this disease among younger people, secondary to the development of CAD. The increasing incidence of CAD among younger people is a result of an evolution towards increasingly sedentary lifestyles, combined with the increased consumption of fast food. Current services can be partly enhanced by expanding existing multi-centre registries and making provision of funds for additional research pertaining to HF and its attendant risk factors.