Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial

OBJECTIVES: The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, and potential effects on parameters of myocardial function of intracoronary infusion of either circulating progenitor cells (CPC) or bone marrow-derived progenitor cells (BMC) in patients with acute myocardial infarction (AMI). BACKGROUND: In animal experiments, therapy with adult progenitor cells was shown to improve vascularization, left ventricular (LV) remodeling, and contractility after AMI. METHODS: A total of 59 patients with AMI were randomly assigned to receive either CPC (n = 30) or BMC (n = 29) into the infarct artery at 4.9 +/- 1.5 days after AMI. RESULTS: Intracoronary progenitor cell application did not incur any measurable ischemic myocardial damage, but one patient experienced distal embolization before cell therapy. During hospital follow-up, one patient in each cell group developed myocardial infarction; one of these patients died of cardiogenic shock. No further cardiovascular events, including ventricular arrhythmias or syncope, occurred during one-year follow-up. By quantitative LV angiography at four months, LV ejection fraction (EF) significantly increased (50 +/- 10% to 58 +/- 10%; p < 0.001), and end-systolic volumes significantly decreased (54 +/- 19 ml to 44 +/- 20 ml; p < 0.001), without differences between the two cell groups. Contrast-enhanced magnetic resonance imaging after one year revealed an increased EF (p < 0.001), reduced infarct size (p < 0.001), and absence of reactive hypertrophy, suggesting functional regeneration of the infarcted ventricles. CONCLUSIONS: Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and feasible in patients after AMI successfully revascularized by stent implantation. Both the excellent safety profile and the observed favorable effects on LV remodeling, provide the rationale for larger randomized double-blind trials.     

Bone-marrow-derived cell transfer after ST-elevation myocardial infarction: lessons from the BOOST trial

Emerging evidence suggests that bone-marrow-derived stem and progenitor cells can be used to improve cardiac function after acute myocardial infarction. We tested this concept in the randomized, controlled, BOOST (bone marrow transfer to enhance ST-elevation infarct regeneration) clinical trial. Following successful percutaneous coronary intervention for acute ST-elevation myocardial infarction, patients received an intracoronary transfer of autologous bone marrow cells (BMCs). After 6 months, global left ventricular ejection fraction, as determined by magnetic resonance imaging, was significantly improved in the BMC-treated group compared with the control group. BMC transfer enhanced left ventricular systolic function, primarily in myocardial segments adjacent to the infarcted area, and also had a positive effect on diastolic function. BMC transfer did not increase the risk of adverse clinical events and did not promote in-stent re-stenosis or proarrhythmic effects. In principle, the effects of BMC transfer on ejection fraction were sustained at 18-month follow-up. Notably, radioactive labeling of BMCs and positron emission tomography showed that these beneficial effects are achieved with limited cardiac homing of BMCs after intracoronary application. Taken together, our studies indicate that intracoronary transfer of autologous BMCs is a safe, promising, and novel approach to further improving systolic function in patients with successful reperfusion after acute myocardial infarction.     

Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial.

AIMS: We have recently shown in the randomized-controlled BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial that intracoronary autologous bone marrow cell (BMC) transfer improves left ventricular (LV) ejection fraction recovery in patients after acute myocardial infarction (AMI). However, the impact of BMC therapy on LV diastolic function in patients after AMI has remained uncertain. METHODS AND RESULTS: Using (tissue) Doppler echocardiography, we evaluated the effects of BMC transfer on LV diastolic function in patients enrolled in the BOOST trial. After successful primary percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (MI), patients were randomized to a control (n = 29) or BMC transfer group (n = 30). Diastolic function was determined 4.5+/-1.5 days after PCI, at 6 months, and at 18 months by measuring transmitral flow velocities (E/A ratio), diastolic myocardial velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). All analyses were performed in a blinded fashion. There was an overall effect of BMC transfer on E/A [0.33+/-0.12; 95% confidence interval (CI): 0.09-0.57; P = 0.008] and Ea/Aa ratios (0.29+/-0.14; 95% CI: 0.01-0.57; P = 0.04). In contrast, we found no effect of BMC transfer on DT (-5+/-14 ms; 95% CI: -33 to 22; P = 0.70), IVRT (-7+/-7 ms; 95% CI: -20 to 6; P = 0.29), and E/Ea ratio (0.35+/-0.14; 95% CI: -0.92 to 1.62; P = 0.57). CONCLUSION: Intracoronary autologous BMC transfer improves echocardiographic parameters of diastolic function in patients after AMI.     

Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction.

BACKGROUND: Transplantation of non-expanded peripheral blood mononuclear cells (PBMNCs) enhances neovessel formation in ischemic myocardium and limbs by releasing angiogenic factors. This study was designed to examine whether intracoronary transplantation of PBMNCs improves cardiac function after acute myocardial infarction (AMI). METHODS AND RESULTS: After successful percutaneous coronary intervention (PCI) for a ST-elevation AMI with occlusion of proximal left anterior descending coronary artery within 24 h, patients were assigned to either a control group or the PBMNC group that received intracoronary infusion of PBMNCs within 5 days after PCI. PBMNCs were obtained from patients by COBE spectra-apheresis and concentrated to 10 ml, 3.3 ml of which was infused via over-the-wire catheter. The primary endpoint was the global left ventricular ejection fraction (LVEF) change from baseline to 6 months' follow-up. The data showed that the absolute increase in LVEF was 7.4% in the control group and 13.4% (p=0.037 vs control) in the PBMNC group. Cell therapy resulted in a greater tendency of DeltaRegional ejection fraction (EF) or significant improvement in the wall motion score index and Tc-99m-tetrofosmin perfusion defect score associated with the infarct area, compared with controls. Moreover, intracoronary administration of PBMNCs did not exacerbate either left ventricular (LV) end-diastolic and end-systolic volume expansion or high-risk arrhythmia, without any adverse clinical events. CONCLUSION: Intracoronary infusion of non-expanded PBMNCs promotes improvement of LV systolic function. This less invasive and more feasible approach to collecting endothelial progenitor cells may provide a novel therapeutic option for improving cardiac function after AMI.     

Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials.

OBJECTIVES: We aimed to perform a meta-analysis of clinical trials on intracoronary cell therapy after acute myocardial infarction (AMI). BACKGROUND: Intracoronary cell therapy continues to be evaluated in the setting of AMI with variable impact on left ventricular ejection fraction (LVEF). METHODS: We searched the CENTRAL, mRCT, and PubMed databases for controlled trials reporting on intracoronary cell therapy performed in patients with a recent AMI (< or =14 days), revascularized percutaneously, with follow-up of > or =3 months. The primary end point was change in LVEF, and secondary end points were changes in infarct size, cardiac dimensions, and dichotomous clinical outcomes. RESULTS: Ten studies were retrieved (698 patients, median follow-up 6 months), and pooling was performed with random effect. Subjects that received intracoronary cell therapy had a significant improvement in LVEF (3.0% increase [95% confidence interval (CI) 1.9 to 4.1]; p < 0.001), as well as a reduction in infarct size (-5.6% [95% CI -8.7 to -2.5]; p < 0.001) and end-systolic volume (-7.4 ml [95% CI -12.2 to -2.7]; p = 0.002), and a trend toward reduced end-diastolic volume (-4.6 ml [95% CI -10.4 to 1.1]; p = 0.11). Intracoronary cell therapy was also associated with a nominally significant reduction in recurrent AMI (p = 0.04) and with trends toward reduced death, rehospitalization for heart failure, and repeat revascularization. Meta-regression suggested the existence of a dose-response association between injected cell volume and LVEF change (p = 0.066). CONCLUSIONS: Intracoronary cell therapy following percutaneous coronary intervention for AMI appears to provide statistically and clinically relevant benefits on cardiac function and remodeling. These data confirm the beneficial impact of this novel therapy and support further multicenter randomized trials targeted to address the impact of intracoronary cell therapy on overall and event-free long-term survival.     

Lack of regeneration of myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans with large anterior myocardial infarctions

BACKGROUND: Experimental and preliminary clinical data suggest that transplantation of autologous bone marrow cells (BMC) may contribute to regeneration of the myocardium after acute myocardial infarction. This approach should be tested in patients with large infarctions in whom a positive effect would be most beneficial. METHODS AND RESULTS: After successful recanalization within 5.9 +/- 2.5 h and stent implantation in five patients with a large acute anterior myocardial infarction (AMI), the patients received autologous mononuclear BMCs via a balloon catheter placed into the left anterior descending artery 6.3 +/- 0.4 days after revascularization. At 3-month follow-up, no improvement was observed for left ventricular ejection fraction, regional wall motion in the infarcted zone, contractility index measured via dobutamine stress echocardiography, coronary blood flow reserve and maximal oxygen uptake, respectively. After further follow-up of 12 months, again no change of the left ventricular ejection fraction could be detected. CONCLUSIONS: Intracoronary transplantation of autologous mononuclear BMCs did not improve cardiac function in our patients with large anterior myocardial infarctions after 3 and 12 months.     

地尔硫卓治疗直接经皮冠状动脉介入术无复流的临床研究

目的探讨冠状动脉内注射地尔硫卓治疗直接经皮冠状动脉介入术（PCI）无复流的疗效。方法对23例直接PCI无复流患者给予梗死相关冠脉（IRA）内推注地尔硫卓2-4mg,分别于推注地尔硫卓前及推注后5min,用校正的心肌梗死溶栓治疗临床实验（TIMI）帧数（Corrected TIMI FrameCount,CTFC）评价IRA血流情况。结果23例无复流患者于IRA内注入地尔硫卓后CTFC由（60.45±12.10）帧降至（30.03±8.20）帧（P〈0.001）,其中17例（复流组）IRA血流恢复至TIMI3级,6例（无复流组）IRA血流未恢复,有效率73.91%。结论冠脉内注射地尔硫卓治疗直接PCI无复流能有效地恢复患者IRA血流,可作为治疗无复流的一种方法。     

Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis

BACKGROUND: The results from small clinical studies suggest that therapy with adult bone marrow (BM)-derived cells (BMCs) reduces infarct size and improves left ventricular function and perfusion. However, the effects of BMC transplantation in patients with ischemic heart disease remains unclear. METHODS: We searched MEDLINE, EMBASE, Science Citation Index, CINAHL (Cumulative Index to Nursing and Allied Health), and the Cochrane Central Register of Controlled Trials (CENTRAL) (through July 2006) for randomized controlled trials and cohort studies of BMC transplantation to treat ischemic heart disease. We conducted a random-effects meta-analysis across eligible studies measuring the same outcomes. RESULTS: Eighteen studies (N = 999 patients) were eligible. The adult BMCs included BM mononuclear cells, BM mesenchymal stem cells, and BM-derived circulating progenitor cells. Compared with controls, BMC transplantation improved left ventricular ejection fraction (pooled difference, 3.66%; 95% confidence interval [CI], 1.93% to 5.40%; P<.001); reduced infarct scar size (-5.49%; 95% CI, -9.10% to -1.88%; P = .003); and reduced left ventricular end-systolic volume (-4.80 mL; 95% CI, -8.20 to -1.41 mL; P = .006). CONCLUSIONS: The available evidence suggests that BMC transplantation is associated with modest improvements in physiologic and anatomic parameters in patients with both acute myocardial infarction and chronic ischemic heart disease, above and beyond conventional therapy. Therapy with BMCs seems safe. These results support conducting large randomized trials to evaluate the impact of BMC therapy vs the standard of care on patient-important outcomes.     

Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis for randomized controlled trials

BACKGROUND: Experimental and clinical studies have suggested that intracoronary infusion of bone marrow-derived stem/progenitor cells (BMC) may improve left ventricular function after acute myocardial infarction (AMI). We conducted a systematic review and meta-analysis to investigate the efficacy and safety of BMC therapy on global left ventricular function in AMI. METHODS: A systematic literature search of MEDLINE, Cochrane Controlled Trials Register, EMBASE, Science Citation Index, and PUBMED from their inception to March 2007 was conducted using specific search terms. Reference lists of papers and reviews on the topic were further searched. Finally, six randomized controlled trials that comprised 517 patients were eligible for further meta-analysis. We used a standardized protocol to extract information on the included studies. RESULTS: Compared with the control groups, BMC therapy produced a slight improvement of the follow-up left ventricular ejection fraction (LVEF) [2.53%, 95% confidence interval (CI): 0.67-4.39, P=0.008] between 3 and 6 months. Similarly, BMC therapy also significantly improved the LVEF change from baseline to follow-up [2.88%, 95%CI: 1.69-4.08, P=0.000] compared to control groups, and the heterogeneity across the studies with regards to the follow-up LVEF (P=0.696) and the LVEF change (P=0.179). Major adverse cardiovascular events, including ventricular arrhythmia, rehospitalization for heart failure, and the composite of other cardiovascular events (cardiac death, recurrent myocardial infarction, infarct-vessel revascularization procedure, and stroke), were not significantly different between BMC therapy and control groups [relative risk (RR): 1.19, 95%CI: 0.68-2.06; RR: 1.79, 95%CI: 0.62-5.17; and RR: 1.05, 95%CI: 0.81-1.35, respectively]. CONCLUSION: On the basis of present evidence, intracoronary BMC infusion in patients with AMI seems to be safe and associated with slight improvement of the left ventricular ejection fraction at 3-6 months' follow-up.     

经冠状动脉自体骨髓干细胞移植治疗急性心肌梗死安全性的系统评价

目的 系统评价经冠状动脉自体骨髓干细胞移植(BMSC)治疗急性心肌梗死的安全性.方法 全面检索PubMed、MEDLINE、Cochrane EBM、BIOSIS等数据库.以急性心肌梗死症状出现24 h内成功实施再灌注治疗者为研究对象;试验设计体现随机对照原则;经冠状动脉移植细胞类型为非动员自体BMSC.结果 5项研究入选总病例数620例,随访4～18个月.死亡、再次心肌梗死、血运重建等临床不良事件及其联合终点的发生均显示出BMSC移植的有益趋势,但差异无统计学意义.分层分析显示,BMSC移植显著降低急性心肌梗死1年后死亡、血运重建、因心力衰竭再入院或再次心肌梗死联合终点发生率(OR=0.45,95%CI 0.28～0.74,P=0.002);急诊经皮冠状动脉介入治疗(PCI)术后4～7 d行干细胞移植可降低血运重建发生率(OR=0.60,95%CI 0.37～0.97,P=0.04)及死亡、血运重建或再次心肌梗死联合发生率(OR=0.58,95%CI 0.37～0.91,P=0.02),而术后24 h内移植可显著增加血运重建和再次心肌梗死的联合发生率(OR=2.56,95%CI 1.03～6.34,P=0.04).结论 经冠状动脉自体BMSC移植治疗急性心肌梗死是安全的,而且急诊PCI术后4～7 d移植较术后24 h内移植安全性更好.     

Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry

Although intracoronary administration of bone marrow-derived mononuclear progenitor cells (BMCs) may be associated with improved cardiac function in patients with chronic postinfarction heart failure, the impact on prognosis and clinical outcome of these patients is unknown. To identify potential predictors for a favorable clinical outcome, we assessed natriuretic peptide serum levels as objective markers of heart failure and the occurrence of cardiac death in relation to functional capacity of the infused cells in a consecutive series of 121 patients with chronic ischemic heart disease treated with intracoronary infusion of BMCs. Our analyses show that both N-terminal pro-brain natriuretic peptide (NT-proBNP) and N-terminal pro-atrial natriuretic peptide (NT-proANP) serum levels were significantly reduced in patients with established postinfarction heart failure 3 months after transcoronary progenitor cell administration. NT-proBNP serum levels greater than or equal to median (735 pg/mL) at baseline and a high number of infused progenitor cells with colony-forming capacity were the only independent predictors of a favorable response 3 months after intracoronary administration of BMCs. During extended clinical follow-up (577+/-442 days), a total of 14 deaths occurred in the overall patient population. Kaplan-Meier curves for both all cause and cardiac mortality showed that patients receiving a higher number of colony-forming cells were significantly less likely to die than those patients receiving low numbers of colony-forming cells (P=0.01). Most importantly, infusion of a high number of cells with colony-forming capacity was associated with a complete abrogation of increased mortality in patients with elevated NT-proBNP serum levels (> or =735 pg/mL; median) at baseline (P<0.001). Taken together, our results show that patients with objective evidence of postinfarction heart failure demonstrate a significant reduction of both NT-proBNP and NT-proANP serum levels within 3 months following intracoronary infusion of BMCs. Importantly, infusion of progenitor cells with a high functional capacity is associated with a significantly lower mortality during further follow-up.     

Increase of myocardial salvage and left ventricular function recovery with intracoronary abciximab downstream of the coronary occlusion in patients with acute myocardial infarction treated with primary coronary intervention.

In this prospective randomized trial on patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI), we hypothesized that abciximab administered intracoronarily, downstream of the coronary occlusion, leads to a greater degree of myocardial salvage and better left ventricular function recovery compared with the usual abciximab administration. Forty-five consecutive patients with first AMI and infarct-related artery TIMI flow 0-1 undergoing primary PCI were enrolled. Twenty-two patients were randomly assigned to the intracoronary treatment and 23 to the usual treatment. The initial perfusion defect, final infarct size, myocardial salvage, salvage index, and left ventricular function recovery were assessed by serial scintigraphic scans performed at admission and 7 days and 1 month after PCI. Angiographic myocardial blush grade, corrected TIMI frame count, and electrocardiographic ST segment elevation reduction were also assessed as markers of myocardial reperfusion. Final infarct size was significantly smaller (P = 0.043) and salvage index significantly higher (P = 0.003) in the intracoronary treatment group as a result of a greater degree of myocardial salvage (P = 0.0001). The increase of left ventricular ejection fraction at 1 month was significantly higher in the intracoronary treatment patients (P = 0.013). The markers of myocardial reperfusion were also significantly better in the intracoronary treatment group. In patients with AMI and occluded infarct-related artery treated with primary PCI, intracoronary abciximab given just before PCI downstream of the occlusion is associated to a greater degree of myocardial salvage than the usual abciximab protocol. This benefit is mainly related to a substantial reduction in final infarct size, which leads to an improvement in left ventricular ejection fraction.     

Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of "no reflow" phenomenon.

Percutaneous intervention in acute myocardial infarction has been associated with a high incidence of "no reflow," ranging from 11% to 30%, with an increased risk of complications. The role of intracoronary adenosine for the prevention of this phenomenon has not been evaluated fully. We studied the procedural outcomes of 79 patients who underwent percutaneous intervention in the context of acute myocardial infarction. Twenty-eight patients received no intracoronary adenosine, and 51 received intracoronary adenosine boluses (24-48 microg before and after each balloon inflation). Eight patients who were not given adenosine experienced no reflow (28.6%) and higher rates of in-hospital death, while only three of 51 patients (5.9%; P = 0.014) in the adenosine group experienced no reflow. No untoward complications were noted during adenosine infusion. Intracoronary adenosine bolus administration during percutaneous intervention in the context of acute myocardial infarction is easy and safe and may significantly lessen the incidence of no reflow, which may improve the outcome of this procedure.     

Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction.

AIMS: Experimental and clinical pilot studies suggest that intracoronary progenitor cell infusion can improve left ventricular function and remodelling after acute myocardial infarction (AMI). Since progenitor cells are also known to be involved in restenosis development and atherosclerosis progression, an increased restenosis rate may be a risk of intracoronary cell therapy. METHODS: We performed a retrospective study to compare quantitative angiographic measurements of the infarct target vessel in 83 patients with AMI treated with bare metal stent PCI (matched control) and in 83 patients receiving additional intracoronary progenitor cell infusion at a mean of 5 days post-AMI stent PCI and after 4 months. RESULTS: The late loss as a measure of neointima formation was similar between the control and the cell-treated group at follow-up (0.9+/-0.8 vs. 0.9+/-0.7 mm, P=0.9). Moreover, restenosis rate was comparable in both groups (35% control vs. 27% cell-treated group, P=0.2). Multivariable analysis excluded cell therapy as an independent significant predictor of increased late loss (P=0.4), whereas acute gain (P=0.012) and diabetes mellitus (P=0.002) were independent predictors of late loss. Finally, in the cell-treated group, target vessel revascularization rate remained at 28.9% during a median of >3 years of follow-up, thus excluding an effect on atherosclerotic disease progression. CONCLUSION: In patients with AMI successfully treated with bare metal stent PCI, additional intracoronary progenitor cell infusion does not lead to an increased neointima formation within the implanted stent within 4 months or aggravation of atherosclerotic disease progression.     

One-year clinical outcomes with abciximab vs. placebo in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention after pre-treatment with clopidogrel: results of the ISAR-REACT 2 randomized trial.

AIMS: The aim of this study is to investigate whether the benefit of abciximab in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) undergoing percutaneous coronary intervention (PCI) after pre-treatment with 600 mg clopidogrel is sustained at 1 year. METHODS AND RESULTS: We performed 1-year follow-up of 2022 high-risk patients with NSTE-ACS undergoing urgent PCI, who were randomized to abciximab or placebo after pre-treatment with 600 mg clopidogrel in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial. The combined incidence of death, myocardial infarction, or target vessel revascularization at 1 year was the primary outcome analysis. At 1 year, the primary outcome was reached in 23.3% of patients allocated to abciximab vs. 28.0% of patients allocated to placebo [relative risk (RR) 0.80, 95% confidence interval (CI) 0.67-0.95, P = 0.012]. The combined incidence of death or myocardial infarction was 11.6% in patients allocated to abciximab vs. 15.3% in patients allocated to placebo (RR 0.74, 95% CI 0.59-0.94, P = 0.015). CONCLUSION: In high-risk patients with NSTE-ACS undergoing a PCI after pre-treatment with 600 mg clopidogrel, adverse events occurred less frequently with abciximab and the early benefit was maintained at 1 year after administration.     

Impact of nicorandil to prevent reperfusion injury in patients with acute myocardial infarction: Sigmart Multicenter Angioplasty Revascularization Trial (SMART).

BACKGROUND: Nicorandil in conjunction with percutaneous coronary intervention (PCI) has been reported to reduce reperfusion injury events and improve cardiac function in patients with acute myocardial infarction (AMI). This multicenter study was undertaken to determine the effectiveness and optimal administration of nicorandil in AMI patients. METHODS AND RESULTS: Ninety-two patients with first AMI were randomly assigned to 1 of 3 groups: intracoronary administration of nicorandil (Group A), combined intravenous and intracoronary administration of nicorandil (Group B), and no nicorandil administration (Group C). The primary endpoint was a composite of the incidence of reperfusion-induced arrhythmia, chest pain, and no-reflow/slow-reflow. The secondary endpoint was the combined rate of improvement in the Thrombolysis in Myocardial Infarction frame count (cTFC) and ST resolution (STR). A significant difference was observed in the primary endpoint for Group B as compared with Group C (p<0.05). In the meantime, a significant improvement was shown in the secondary endpoint for Group B compared with Group C (p=0.04 and 0.006 for cTFC and STR, respectively). CONCLUSIONS: Combined intravenous and intracoronary administration of nicorandil reduces reperfusion injury during PCI and improves the cTFC and STR in AMI, and appears to be preferable to intracoronary administration alone.     

Bone Marrow Cell Therapy After Acute Myocardial Infarction. Back to Bench, or Ready for an Outcome Trial

Meta-analyses and some randomized clinical trials have shown modest improvement in left ventricular function after intracoronary injection of bone marrow cells (BMC) in patients with acute myocardial infarction (AMI). This has been shown even though several limitations like ignorance about the best cell(s) to use, the optimal dose, an effective administration mode, and the mechanism of action remain. The potential of BMC therapy will not be realized until these hurdles are passed. And even though BMC therapy seems to be relatively safe, it is invasive and expose the patients to the possibility of procedure-related complications. Thus, at the current stage of development, it will probably be better to use resources on more basic research and small- to intermediate-sized clinical trials instead of a large-scale outcome trial.     

The incomplete bucindolol evaluation in acute myocardial infarction Trial (BEAT)

The aim of this study was to evaluate the efficacy of adding the beta-blocker bucindolol to standard therapy shortly after a myocardial infarction in a high-risk population with reduced left ventricular function. METHODS: The study was planned to include 2000 patients with an enzyme confirmed myocardial infarction and severely reduced left ventricular function determined by echocardiography (corresponding to ejection fraction < or =0.35). The primary endpoint was all cause mortality and the secondary endpoints were time to first event of death, progression of heart failure or reinfarction-and the components. The study was closed early due to discontinuation of development of bucindolol by the manufacturer. Therefore, 170 patients were randomised to receive bucindolol and 173 to receive placebo. RESULTS: There were 27 deaths in the bucindolol group and 30 in the placebo group, hazard ratio of bucindolol 0.88 (95% confidence limits 0.5-1.5; P=0.6). There were 9/4 (bucindolol/placebo, P=0.16) heart failure events and 5/17 (P=0.01) reinfarctions in the bucindolol/placebo groups. CONCLUSION: Due to early closure it is unknown whether bucindolol changes mortality in high-risk post myocardial infarct patients when added to best medical therapy. The frequency of reinfarction was significantly reduced.     

10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice

Intracoronary and intramyocardial stem cell therapy aim at the repair of compromised myocardium thereby--as a causal treatment--preventing ventricular remodeling and improving overall performance. Since the first-in-human use of bone marrow stem cells (BMCs) after acute myocardial infarction in 2001, a large number of clinical studies have demonstrated their clinical benefit: BMC therapy can be performed with usual cardiac catheterization techniques in the conscious patient as well as also easily during cardiosurgical interventions. New York Heart Association severity degree of patients as well as physical activity improve in addition to ("on top" of) all other therapeutic regimens. Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous BMC therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials.     

Does intracoronary abciximab improve the outcome of percutaneous coronary interventions? A randomized controlled trial

INTRODUCTION AND OBJECTIVES: It has been clearly demonstrated that abciximab is useful in percutaneous coronary interventions. However, it is not known if intracoronary administration of the initial abciximab bolus improves outcome. Moreover, there may be safety concerns. METHODS: The study was a single-center prospective randomized trial that included all patients undergoing coronary angioplasty involving the use of abciximab. Patients were randomized to either intracoronary or intravenous administration of the abciximab bolus. The primary endpoint was the incidence of major adverse cardiac events (i.e., death, myocardial infarction, or the need for revascularization); secondary endpoints were hemorrhagic complications and the troponin-I level. RESULTS: The study included 137 patients; 72 received an intracoronary abciximab bolus and 65, an intravenous bolus. Clinical characteristics and baseline angiographic findings were similar in the two groups. All patients underwent coronary stent implantation. No difference was observed between the intracoronary bolus group and the intravenous bolus group in type of stent used (drug eluting stent 47.2% vs 50.8%, respectively), total stent length, or final TIMI flow grade (3 vs 2.97, respectively). The intervention success rates were also similar (98.5% vs. 99%, respectively). No complication associated with the administration route was reported. However, the level of the myocardial injury marker troponin I increased significantly in the intravenous bolus group. Clinical follow-up at 1 year did not reveal any difference in the incidence of major adverse cardiac events: 8.5% in the intracoronary bolus group versus 6.2% in the intravenous bolus group. CONCLUSIONS: Intracoronary administration of an abciximab bolus did not appear to be less safe or effective than intravenous administration. Less post-procedural myocardial damage was observed in the intracoronary bolus group.