Redo-aortic valve replacement in prior stentless prosthetic aortic valves: Transcatheter versus surgical approach.

OBJECTIVES: The objective was to compare outcomes of redo-aortic valve replacement (AVR) via surgical or transcatheter approach in prior surgical AVR with large percentage of prior stentless surgical AVR. BACKGROUND: With the introduction of transcatheter aortic valve replacement (TAVR), patients with increased surgical risks now have an alternative to redo surgical AVR (SAVR), known as valve-in-valve (ViV) TAVR. Stentless prosthetic aortic valves present a more challenging implantation for ViV-TAVR given the lack of structural frame. METHODS: We performed a retrospective study of 173 subjects who have undergone SAVR (N = 100) or ViV-TAVR (N = 73) in patients with prior surgical AVR at Wake Forest Baptist Medical Center from 2009 to 2019. Our study received the proper ethical oversight. RESULTS: The average ages in redo-SAVR and ViV-TAVR groups were 58.03 ± 13.86 and 66.57 ± 13.44 years, respectively (p < 0.0001). The redo-SAVR had significantly lower STS (2.78 ± 2.09 and 4.68 ± 5.51, p < 0.01) and Euroscores (4.32 ± 2.98 and 7.51 ± 8.24, p < 0.05). The redo-SAVR group had higher percentage requiring mechanical support (8% vs. 0%, p < 0.05) and vasopressors (53% vs. 0%, p < 0.0001), longer length of stay (13.65 ± 11.23 vs. 5.68 ± 7.64 days, p < 0.0001), and inpatient mortality (16% vs. 2.78%, p < 0.005). At 30-day follow-up, redo-SAVR group had higher rates of acute kidney injury (10% vs. 0%, p < 0.01), however ViV-TAVR group had more new left bundle branch blocks (6.85% vs. 0%, p < 0.05). No significant differences regarding re-hospitalization rates, stroke, or death up to 1-year. CONCLUSION: Although the ViV-TAVR group had higher risk patients, there were significantly fewer procedural complications, shorter length of stay, and similar mortality outcomes up to 1-year follow-up.

A novel technique for postclosure of large-bore sheaths using two Perclose devices.

OBJECTIVES: This study aimed to assess the feasibility, efficacy, and safety of a novel percutaneous postprocedure closure technique for large arterial sheath removal with the use of two Perclose ProGlide (Abbott Vascular Devices, Redwood City, CA) devices. BACKGROUND: Postprocedural closing of large-bore arteriotomies using the Perclose system can be difficult given the subsequent inability of the device to capture sufficient wall tissue. METHODS: Our study was a single-center retrospective analysis of 22 consecutive patients who underwent large arteriotomy closure via the postclosure technique with a 12-16-Fr sheath. Efficacy endpoints included successful deployment of the system and hemostasis. Safety endpoints included the incidence of major or minor vascular complications as defined by the Vascular Academic Research Consortium-2 (VARC-2) definitions at 30-day follow-up. RESULTS: The postclosure technique resulted in 100% technical success rate and no postprocedural bleeding or vascular complications. CONCLUSION: Postclosure technique is a safe, highly effective, and feasible percutaneous method to achieve large-bore arteriotomy hemostasis with low rates of major bleeding or vascular complications and favorable early outcome.

A comparison of valve-in-valve transcatheter aortic valve replacement in failed stentless versus stented surgical bioprosthetic aortic valves.

OBJECTIVES: The objectives of this study were to compare short- and intermediate-term clinical outcomes, procedural complications, TAVR prosthesis hemodynamics, and paravalvular leak (PVL) in stentless and stented groups. BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) is an alternative to surgical redo for bioprosthetic valve failure. There have been limited data on ViV in stentless surgical valves. METHODS: We retrospectively analyzed 40 patients who underwent ViV TAVR in prior surgical bioprosthetic valves at Wake Forest Baptist Medical Center from October 2014 to September 2017. Eighty percent (32/40) ViV TAVRs were in stentless, while 20% (8/40) were in stented bioprosthetic valves. RESULTS: The primary mode of bioprosthetic valve failure for ViV implantation in the stentless group was aortic insufficiency (78%, 25/32), while in the stented group was aortic stenosis (75%, 6/8). The ViV procedure success was 96.9% (31/32) in stentless group and 100% in stented group (8/8). There were no significant differences in all-cause mortality at 30 days between stentless and stented groups (6.9%, 2/31 versus 0%, 0/8, P = 0.33) and at 1 year (0%, 0/25 versus 0%, 0/5). In the stentless group, 34.4% (11/32) required a second valve compared to the stented group of 0% (0/8). There was a significant difference in the mean aortic gradient at 30-day follow-up (12.33 ± 6.33 mmHg and 22.63 ± 8.45 mmHg in stentless and stented groups, P < 0.05) and at 6-month follow-up (9.75 ± 5.07 mmHg and 24.00 ± 11.28 mmHg, P < 0.05), respectively. CONCLUSIONS: ViV in the stentless bioprosthetic aortic valve has excellent procedural success and intermediate-term results. Our study shows promising data that may support the application of TAVR in stentless surgical aortic valve. However, further and larger studies need to further validate our single center's experience.

Comparison of paravalvular aortic leak characteristics in the Medtronic CoreValve versus Edwards Sapien Valve: Paravalvular aortic leak characteristics.

OBJECTIVES: Temporally quantify and localize paravalvular aortic leak (PVL) after transcatheter aortic valve replacement (TAVR) in the Medtronic CoreValve (MCV) versus the Edwards Sapien Valve (ESV). BACKGROUND: In order to increase the precision of THV selection and PVL intervention, an understanding of PVL characteristics is essential. METHODS: The frequency, severity, and location of post-TAVR PVL were evaluated with transthoracic echocardiography pre-discharge, one month, and one-year post-procedure in 202 patients receiving a MCV (N = 120) or ESV (N = 81). This was done through application of a clock face to the short axis of the aortic valve in order to divide the area into three tertiles. RESULTS: Pre-discharge differences between PVL frequency and severity in the MCV and ESV lost significance over time. Localizing these trends, MCV PVL frequency and severity significantly decreased in the first and third tertiles during most time periods while PVL in the second tertile of the MCV or in any of the tertiles of the ESV failed to improve. Presence of pre-discharge PVL was predictive of 30-day HF readmission and/or death (OR = 3.16, 95% CI: 0.99-10.12). Presence of pre-discharge and 30-day PVL was predictive of 1-year HF readmissions and/or death (OR = 2.12, 95% CI: 1.09-4.13 and OR = 1.99, 95% CI: 0.96-4.12). CONCLUSIONS: When comparing the MCV and ESV, not all locations of PVL improve equally over time, which has implications for heart failure readmissions. This could be used to influence valve selection and to identify cases in which earlier intervention on PVL may be appropriate.

TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis.

RATIONALE: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function. OBJECTIVE: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. METHODS AND RESULTS: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). CONCLUSIONS: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment-elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial.

BACKGROUND: Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. METHODS: To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. RESULTS: In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. CONCLUSIONS: In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial.

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

Bone marrow characteristics associated with changes in infarct size after STEMI: a biorepository evaluation from the CCTRN TIME trial.

RATIONALE: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. OBJECTIVE: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation-myocardial infarction. METHODS AND RESULTS: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31(+) BMCs (P=0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays (P=0.033 and P=0.032, respectively). CONCLUSIONS: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation-myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation-myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. CLINICAL TRIAL REGISTRATION INFORMATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes.

RATIONALE: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). OBJECTIVE: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. METHODS AND RESULTS: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%-2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b(+) cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus -0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34(+) percentage in patients with chronic IHD correlated with decrement in LVEF (-2.9% versus +0.7%; P=0.0355). CONCLUSIONS: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. CLINICAL TRIAL REGISTRATIONS URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005.

Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

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.

LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction.

A realistic goal for cardiac cell therapy may be to attenuate left ventricular remodeling following acute myocardial infarction to prevent the development of congestive heart failure. Initial clinical trials of cell therapy have delivered cells 1 to 7 days after acute myocardial infarction. However, many patients at risk of developing congestive heart failure may not be ready for cell delivery at that time-point because of clinical instability or hospitalization at facilities without access to cell therapy. Experience with cell delivery 2 to 3 weeks after acute myocardial infarction has not to date been explored in a clinical trial. The objective of the LateTIME study is to evaluate by cardiac magnetic resonance the effect on global and regional left ventricular function, between baseline and 6 months, of a single intracoronary infusion of 150 × 106 autologous bone marrow mononuclear cells (compared with placebo) when that infusion is administered 2 to 3 weeks after moderate-to-large acute myocardial infarction. The 5 clinical sites of the Cardiovascular Cell Therapy Research Network (CCTRN) will enroll a total of 87 eligible patients in a 2:1 bone marrow mononuclear cells-to-placebo patient ratio; these 87 will have undergone successful percutaneous coronary intervention of a major coronary artery and have left ventricular ejection fractions ≤0.45 by echocardiography. When the results become available, this study should provide insight into the clinical feasibility and appropriate timing of autologous cell therapy in high-risk patients after acute myocardial infarction and percutaneous coronary intervention.

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design.

BACKGROUND: The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. TRIAL DESIGN: The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment. RESULTS: After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. CONCLUSIONS: The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.

Development of a network to test strategies in cardiovascular cell delivery: the NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN).

The emerging sciences of stem cell biology and cellular plasticity have led to the development of cell-based therapies for advanced human disease. Pre-clinical studies which defined the potential of bone marrow-derived mononuclear cells to repair damaged and dysfunctional myocardium led to the rapid advancement of these strategies to the clinic. Such rapid advancement has led to controversy regarding the appropriate conduct of such studies. In the United States, the National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Research Network (CCTRN) to facilitate the early translation of clinical trials of cell therapy for left ventricular dysfunction. The premise upon which the CCTRN was established was that multiple clinical trial sites would interact effectively with a Data Coordinating Center to perform early phase 1 and 2 clinical trials within a highly coordinated network structure. In order to develop this network, the unmet needs of the community needed to be defined, the clinical trials identified, and the structure to perform the studies needed to be established. This manuscript highlights the challenges in the development of the CCTRN and the approaches faced to define a network to perform clinical trials in human cell therapy of cardiovascular disease.

Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction.

Several previous studies have demonstrated that administration of autologous bone marrow-derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction (AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction

Treatment of unprotected left main coronary artery stenosis in a 5-year-old heart transplant patient using a sirolimus-eluting stent.

Cardiac allograft vasculopathy is the most common cause of long-term graft failure in adult and pediatric heart transplant recipients. In the absence of a specific treatment for this condition, percutaneous revascularization has been the main palliative treatment in the adult population. Revascularization of pediatric patients, however, is more problematic secondary to the lack of a large pool of outcome data and the encounter of special technical challenges. We present the case of a 5-year-old girl who presented with severe cardiac allograft vasculopathy of her left main coronary artery and was treated with sirolimus stent placement.