Jay H. Traverse

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction

OBJECTIVES Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). BACKGROUND Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. METHODS We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. RESULTS Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. CONCLUSIONS Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina : A phase I/IIa double-blind, randomized controlled trial

Background— A growing population of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Preclinical studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium, which enhances perfusion and function. Methods and Results— Twenty-four patients (19 men and 5 women aged 48 to 84 years) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization were enrolled in a double-blind, randomized (3:1), placebo-controlled dose-escalating study. Patients received granulocyte colony-stimulating factor 5 &mgr;g · kg−1 · d−1 for 5 days with leukapheresis on the fifth day. Selection of CD34+ cells was performed with a Food and Drug Administration–approved device. Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells (versus saline). The total dose of cells was distributed in 10 intramyocardial, transendocardial injections. Patients were required to have an implantable cardioverter-defibrillator or to temporarily wear a LifeVest wearable defibrillator. No incidence was observed of myocardial infarction induced by mobilization or intramyocardial injection. The intramyocardial injection of cells or saline did not result in cardiac enzyme elevation, perforation, or pericardial effusion. No incidence of ventricular tachycardia or ventricular fibrillation occurred during the administration of granulocyte colony-stimulating factor or intramyocardial injections. One patient with a history of sudden cardiac death/ventricular tachycardia/ventricular fibrillation had catheter-induced ventricular tachycardia during mapping that required cardioversion. Serious adverse events were evenly distributed. Efficacy parameters including angina frequency, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class showed trends that favored CD34+ cell–treated patients versus control subjects given placebo. Conclusions— A randomized trial of intramyocardial injection of autologous CD34+ cells in patients with intractable angina was completed that provides evidence for feasibility, safety, and bioactivity. A larger phase IIb study is currently under way to further evaluate this therapy.

A Regional System to Provide Timely Access to Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction

Background— Percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is superior to fibrinolysis when performed in a timely manner in high-volume centers. Recent European trials suggest that transfer for PCI also may be superior to fibrinolysis and increase access to PCI. In the United States, transfer times are consistently long; therefore, many believe a transfer for PCI strategy for STEMI is not practical. Methods and Results— We developed a standardized PCI-based treatment system for STEMI patients from 30 hospitals up to 210 miles from a PCI center. From March 2003 to November 2006, 1345 consecutive STEMI patients were treated, including 1048 patients transferred from non-PCI hospitals. The median first door-to-balloon time for patients <60 miles (zone 1) and 60 to 210 miles (zone 2) from the PCI center was 95 minutes (25th and 75th percentiles, 82 and 116 minutes) and 120 minutes (25th and 75th percentiles, 100 and 145 minutes), respectively. Despite the high-risk unselected patient population (cardiogenic shock, 12.3%; cardiac arrest, 10.8%; and elderly [≥80 years of age], 14.6%), in-hospital mortality was 4.2%, and median length of stay was 3 days. Conclusions— Rapid transfer of STEMI patients from community hospitals up to 210 miles from a PCI center is safe and feasible using a standardized protocol with an integrated transfer system.

Intramyocardial, Autologous CD34+ Cell Therapy for Refractory Angina

Rationale: A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function. Objective: Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options. Methods and Results: In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×105 or 5×105 cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients. Conclusions: Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (105 cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart

Background— Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results— Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)–induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased ≈4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3′-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions— Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.

Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis

AIMS The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. METHODS AND RESULTS We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (-3.17 mL/m², 95% CI: -4.86 to -1.47, P < 0.001; -2.60 mL/m², 95% CI -3.84 to -1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥ 55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥ 40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes. CONCLUSION Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therapy.

Circadian Dependence of Infarct Size and Left Ventricular Function After ST Elevation Myocardial Infarction

Rationale: In rodents, infarct size after ischemia/reperfusion exhibits a circadian dependence on the time of coronary occlusion. It is not known if a similar circadian dependence of infarct size occurs in humans. Objective: To determine if humans exhibit a circadian dependence of infarct size in the setting of ST elevation myocardial infarction (STEMI). Methods and Results: A retrospective analysis of 1031 patients with STEMI referred for primary percutaneous coronary intervention with known ischemic times between 1 and 6 hours identified 165 patients with occluded arteries on presentation without evidence of preinfarction angina or collateral blood flow. Both ischemic duration and angiographic area at risk were not dependent on time of infarct onset. We observed that the extent of infarct size measured by creatine kinase release was significantly associated with time of day onset of infarction (P<0.0001). The greatest myocardial injury occurred at 1:00 AM onset of ischemia and 5:00 AM onset of reperfusion, with the peak creatine kinase measured at the peak of the curve being 82% higher than that recorded at the trough. Similarly, left ventricular ejection fraction measured within 2 days of infarction was also dependent on time of onset of STEMI with the absolute left ventricular ejection fraction at peak >7% higher than at trough (43% vs 51%; P<0.03). These findings were supported by a subgroup of patients (n=45) who underwent cardiac MRI measurements of infarct size and area-at-risk measurements. Conclusions: The results of this study demonstrate for the first time in humans that myocardial infarct size and left ventricular function after STEMI have a circadian dependence on the time of day onset of ischemia.