High bitrate data transmission in the 8-14 µm atmospheric window using an external Stark-effect modulator with digital equalization.

High bitrate mid-infrared links using simple (NRZ) and multi-level (PAM-4) data coding schemes have been realized in the 8 µm to 14 µm atmospheric transparency window. The free space optics system is composed of unipolar quantum optoelectronic devices, namely a continuous wave quantum cascade laser, an external Stark-effect modulator and a quantum cascade detector, all operating at room-temperature. Pre- and post-processing are implemented to get enhanced bitrates, especially for PAM-4 where inter-symbol interference and noise are particularly detrimental to symbol demodulation. By exploiting these equalization procedures, our system, with a full frequency cutoff of 2 GHz, has reached transmission bitrates of 12 Gbit/s NRZ and 11 Gbit/s PAM-4 fulfilling the 6.25 % overhead hard-decision forward error correction threshold, limited only by the low signal-to-noise ratio of our detector.

Optical amplification-free deep reservoir computing-assisted high-baudrate short-reach communication.

An optical amplification-free deep reservoir computing (RC)-assisted high-baudrate intensity modulation direct detection (IM/DD) system is experimentally demonstrated using a 100G externally modulated laser operated in C-band. We transmit 112 Gbaud 4-level pulse amplitude modulation (PAM4) and 100 Gbaud 6-level PAM (PAM6) signals over a 200-m single-mode fiber (SMF) link without any optical amplification. The decision feedback equalizer (DFE), shallow RC, and deep RC are adopted in the IM/DD system to mitigate impairment and improve transmission performance. Both PAM transmissions over a 200-m SMF with bit error rate (BER) performance below 6.25% overhead hard-decision forward error correction (HD-FEC) threshold are achieved. In addition, the BER of the PAM4 signal is below the KP4-FEC limit after 200-m SMF transmission enabled by the RC schemes. Thanks to the use of a multiple-layer structure, the number of weights in deep RC has been reduced by approximately 50% compared with the shallow RC, whereas the performance is comparable. We believe that the optical amplification-free deep RC-assisted high-baudrate link has a promising application in intra-data center communications.

Simultaneous modulation format identification and OSNR monitoring based on optoelectronic reservoir computing.

An approach for simultaneous modulation format identification (MFI) and optical signal-to-noise ratio (OSNR) monitoring in digital coherent optical communications is proposed based on optoelectronic reservoir computing (RC) and the signal's amplitude histograms (AHs) obtained after the adaptive post-equalization. The optoelectronic RC is implemented using a Mach-Zehnder modulator and optoelectronic delay feedback loop. We investigate the performance of the proposed model with the number of symbols, bins of AHs and the hyperparameters of optoelectronic RC. The results show that 100% MFI accuracy can be achieved simultaneously with accurate OSNR estimation for different modulation formats under study. The lowest achievable OSNR estimation mean absolute errors for the dual-polarization (DP)-quadrature phase-shift keying signal, the DP-16-ary quadrature amplitude modulation (16QAM) signal, and the DP-64QAM signal are 0.2 dB, 0.32 dB and 0.53 dB, respectively. The robustness of the proposed scheme is also evaluated when the optoelectronic RC is in presence of additive white Gaussian noises. Then, a proof of concept experiment is demonstrated to further verify our proposed method. The proposed approach offers a potential solution for next-generation intelligent optical performance monitoring in the physical layer.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

400-Gb/s direct modulation using a DFB+R laser.

We demonstrate a direct-modulation and direct-detection system with a back-to-back line rate of 411.6 (net bit rate of 337.5) Gb/s using a 65 GHz DFB+R laser. The O-band laser with a chirp parameter of 0.6 supports dispersion-tolerant transmissions up to 15 km without an optical amplifier.

PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI.

RATIONALE: Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. OBJECTIVE: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. METHODS AND RESULTS: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. CONCLUSIONS: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364.

Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.

Aims: Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells. Methods and results: Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion: Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

Real-time 100 Gbps/λ/core NRZ and EDB IM/DD transmission over multicore fiber for intra-datacenter communication networks.

A BiCMOS chip-based real-time intensity modulation/direct detection spatial division multiplexing system is experimentally demonstrated for both optical interconnects. 100 Gbps/λ/core electrical duobinary (EDB) transmission over 1 km 7-core multicore fiber (MCF) is carried out, achieving KP4 forward error correction (FEC) limit (BER < 2E-4). Using optical dispersion compensation, 7 × 100 Gbps/λ/core transmission of both non-return-to-zero (NRZ) and EDB signals over 10 km MCF transmission is achieved with BER lower than 7% overhead hard-decision FEC limit (BER < 3.8E-3). The integrated low complexity transceiver IC and analog signal processing approach make such a system highly attractive for the high-speed intra-datacenter interconnects.

Nonlinearity-aware 200 Gbit/s DMT transmission for C-band short-reach optical interconnects with a single packaged electro-absorption modulated laser.

We experimentally demonstrate the transmission of a 200 Gbit/s discrete multitone (DMT) at the soft forward error correction limit in an intensity-modulation direct-detection system with a single C-band packaged distributed feedback laser and traveling-wave electro absorption modulator (DFB-TWEAM), digital-to-analog converter and photodiode. The bit-power loaded DMT signal is transmitted over 1.6 km standard single-mode fiber with a net rate of 166.7 Gbit/s, achieving an effective electrical spectrum efficiency of 4.93 bit/s/Hz. Meanwhile, net rates of 174.2 Gbit/s and 179.5 Gbit/s are also demonstrated over 0.8 km SSMF and in an optical back-to-back case, respectively. The feature of the packaged DFB-TWEAM is presented. The nonlinearity-aware digital signal processing algorithm for channel equalization is mathematically described, which improves the signal-to-noise ratio up to 3.5 dB.

Public unawareness of physician reimbursement.

OBJECTIVES: To assess subjects' perception of healthcare costs and physician reimbursement. BACKGROUND: The lack of transparency in healthcare reimbursement leaves patients and physicians unaware of the distribution of health care dollars. METHODS: Anonymous survey-based study by means of convenience sampling. Participants were asked to estimate the total hospital cost and physician fee for one of the six medical procedures (n = 250). RESULTS: On the average for all 6 procedures, patients estimated the total cost was $36,177, ∼1,540% more than the actual Medicare rate of $7,333. Similarly, patients estimated the physician fee was $7,694, 1,474% more the actual Medicare rate of $589. CONCLUSION: Patients' perception of the total cost and physician fee are significantly higher than Medicare rates for all 6 procedures. This lack of insight may have widespread negative implications on the patient-physician relationship, on political trends to reduce physician reimbursement, and on a physician's desire to continue practicing medicine.

Digital mobile fronthaul employing differential pulse code modulation with suppressed quantization noise.

A differential pulse code modulation (DPCM) based digital mobile fronthaul architecture is proposed and experimentally demonstrated. By using a linear predictor in the DPCM encoding process, the quantization noise can be effectively suppressed and a prediction gain of 7~8 dB can be obtained. Experimental validation is carried out with a 20 km 15-Gbaud/λ 4-level pulse amplitude modulation (PAM4) intensity modulation and direct detection system. The results verify the feasibility of supporting 163, 122, 98, 81 20-MHz 4, 16, 64, 256 QAM based antenna-carrier (AxC) containers with only 3, 4, 5, 6 quantization bits at a sampling rate of 30.72MSa/s in LTE-A environment. Further increasing the number of quantization bits to 8 and 9, 1024 quadrature amplitude modulation (1024 QAM) and 4096 QAM transmission can be realized with error vector magnitude (EVM) lower than 1% and 0.5%, respectively. The supported number of AxCs in the proposed DPCM-based fronthaul is increased and the EVM is greatly reduced compared to the common public radio interface (CPRI) based fronthaul that uses pulse code modulation. Besides, the DPCM-based fronthaul is also experimentally demonstrated to support universal filtered multicarrier signal that is one candidate waveform for the 5th generation mobile systems.

Gigabit free-space multi-level signal transmission with a mid-infrared quantum cascade laser operating at room temperature.

Gigabit free-space transmissions are experimentally demonstrated with a quantum cascaded laser (QCL) emitting at mid-wavelength infrared of 4.65 µm, and a commercial infrared photovoltaic detector. The QCL operating at room temperature is directly modulated using on-off keying and, for the first time, to the best of our knowledge, four- and eight-level pulse amplitude modulations (PAM-4, PAM-8). By applying pre- and post-digital equalizations, we achieve up to 3 Gbit/s line data rate in all three modulation configurations with a bit error rate performance of below the 7% overhead hard decision forward error correction limit of 3.8×10-3. The proposed transmission link also shows a stable operational performance in the lab environment.

The Athena trials: Autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction.

OBJECTIVE: To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. BACKGROUND: Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. METHODS: The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. RESULTS: Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. -9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (-21.6 + 13.9 vs. -5.5 + 23.8, P = 0.038). CONCLUSIONS: A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

Gastrointestinal Bleeding Due to Gastrointestinal Tract Malignancy: Natural History, Management, and Outcomes.

BACKGROUND: Gastrointestinal (GI) tumor bleeding can vary from occult bleeding to massive hemorrhage and can be the presenting sign of malignancy. AIMS: Our primary aims were to: (1) characterize the natural history, treatment, and outcomes in patients with GI tumor bleeding and (2) compare and contrast bleeding in upper GI (UGI)/small bowel (SB) and lower GI malignancies. METHODS: Patients with endoscopically confirmed tumor bleeding were identified through search of consecutive electronic medical records: Bleeding was determined by the presence of melena, hematochezia, hematemesis, or fecal occult blood. Comprehensive clinical and management data were abstracted. RESULTS: A total of 354 patients with GI tumors were identified: 71 had tumor bleeding (42 UGI/SB and 29 colonic). GI bleeding was the initial presenting symptom of malignancy in 55/71 (77%) of patients; 26/71 patients had widely metastatic disease at presentation. Further, 15 of 26 patients with metastatic disease presented with GI bleeding. Visible bleeding was present in 14/42 (33%) and 4/29 (14%) of UGI/SB and colonic tumors, respectively. Endoscopic hemostasis was attempted in 10 patients, and although initial control was successful in all, bleeding recurred in all of these patients. The most common endoscopic lesion was clean-based tumor ulceration. Overall mortality at 1 year was 57% for esophageal/gastric, 14% for SB, and 33% for colonic tumors. CONCLUSIONS: When patients with GI malignancy present with GI bleeding, it is often the index symptom. Initial endoscopic hemostasis is often successful, but rebleeding is typical. Esophageal and gastric tumors carry the poorest prognosis, with a high 1-year mortality rate.

Impact of local oscillator frequency noise on coherent optical systems with electronic dispersion compensation.

A theoretical investigation of the equalization-enhanced phase noise (EEPN) and its mitigation is presented. We show with a frequency domain analysis that the EEPN results from the non-linear inter-mixing between the sidebands of the dispersed signal and the noise sidebands of the local oscillator. It is further shown and validated with system simulations that the transmission penalty is mainly due to the slow optical frequency fluctuations of the local oscillator. Hence, elimination of the frequency noise below a certain cut-off frequency significantly reduces the transmission penalty, even when frequency noise would otherwise cause an error floor. The required cut-off frequency increases linearly with the white frequency noise level and hence the linewidth of the local oscillator laser, but is virtually independent of the symbol rate and the accumulated dispersion.

Artificial intelligence coronary computed tomography, coronary computed tomography angiography using fractional flow reserve, and physician visual interpretation in the per-vessel prediction of abnormal invasive adenosine fractional flow reserve.

Aims: A comparison of diagnostic performance comparing AI-QCTISCHEMIA, coronary computed tomography angiography using fractional flow reserve (CT-FFR), and physician visual interpretation on the prediction of invasive adenosine FFR have not been evaluated. Furthermore, the coronary plaque characteristics impacting these tests have not been assessed. Methods and results: In a single centre, 43-month retrospective review of 442 patients referred for coronary computed tomography angiography and CT-FFR, 44 patients with CT-FFR had 54 vessels assessed using intracoronary adenosine FFR within 60 days. A comparison of the diagnostic performance among these three techniques for the prediction of FFR ≤ 0.80 was reported. The mean age of the study population was 65 years, 76.9% were male, and the median coronary artery calcium was 654. When analysing the per-vessel ischaemia prediction, AI-QCTISCHEMIA had greater specificity, positive predictive value (PPV), diagnostic accuracy, and area under the curve (AUC) vs. CT-FFR and physician visual interpretation CAD-RADS. The AUC for AI-QCTISCHEMIA was 0.91 vs. 0.76 for CT-FFR and 0.62 for CAD-RADS ≥ 3. Plaque characteristics that were different in false positive vs. true positive cases for AI-QCTISCHEMIA were max stenosis diameter % (54% vs. 67%, P < 0.01); for CT-FFR were maximum stenosis diameter % (40% vs. 65%, P < 0.001), total non-calcified plaque (9% vs. 13%, P < 0.01); and for physician visual interpretation CAD-RADS ≥ 3 were total non-calcified plaque (8% vs. 12%, P < 0.01), lumen volume (681 vs. 510 mm3, P = 0.02), maximum stenosis diameter % (40% vs. 62%, P < 0.001), total plaque (19% vs. 33%, P = 0.002), and total calcified plaque (11% vs. 22%, P = 0.003). Conclusion: Regarding per-vessel prediction of FFR ≤ 0.8, AI-QCTISCHEMIA revealed greater specificity, PPV, accuracy, and AUC vs. CT-FFR and physician visual interpretation CAD-RADS ≥ 3.

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.

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 (1×10(5) or 5×10(5) 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 (10(5) 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.

Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: an analysis from ACT34-CMI.

BACKGROUND: Cell therapy is a promising therapeutic for a variety of cardiovascular conditions including refractory angina. Elevation of cardiac biomarkers during cell delivery has been frequently described, but the clinical implications have never been studied. METHODS: ACT34-CMI was a randomized double-blind study assessing the use of intramyocardial delivery of autologous CD34(+) cells for the treatment of refractory angina. Patients (n = 167) underwent G-CSF-mediated (5 µg/[kg day] × 5 days) stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5)/kg or 5 × 10(5)/kg CD34(+) cells or placebo. Troponin and creatinine kinase MB were assessed at baseline (n = 161), after cell mobilization and apheresis (n = 153 and 143, respectively), and post-intramyocardial injection (n = 155 and 141, respectively). Major adverse cardiac events (MACE) included death, myocardial infarction, acute congestive heart failure, urgent revascularization, or sustained ventricular arrhythmia. RESULTS: Seven (4.3%) subjects had troponin above the upper limits of normal (ULN) at baseline. Thirty-four (22.2%) and 11 (7.2%) subjects had troponin levels > ULN or >3× ULN after cell mobilization and apheresis, whereas 72 (46.1%) and 39 (25.2%) subjects had troponin elevations > ULN or >3× ULN, respectively, after intramyocardial injections. Age, but no other preprocedural factors, was predictive of troponin elevation. Periprocedural troponin elevation was not associated with an increased risk of MACE during 1 year, especially in cell therapy-treated patients. CONCLUSIONS: Troponin elevation is common during stem cell harvesting and intramyocardial administration, is usually asymptomatic, and does not appear to be associated with long-term MACE in subjects undergoing stem cell mobilization and intramyocardial injection.

A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction.

BACKGROUND: We sought to determine the safety and preliminary efficacy of transcatheter intramyocardial administration of myoblasts in patients with heart failure (HF). METHODS: MARVEL is a randomized placebo-controlled trial of image-guided, catheter-based intramyocardial injection of placebo or myoblasts (400 or 800 million) in patients with class II to IV HF and ejection fraction <35%. Primary end points were frequency of serious adverse events (safety) and changes in 6-minute walk test and Minnesota Living With HF score (efficacy). Of 330 patients intended for enrollment, 23 were randomized (MARVEL-1) before stopping the study for financial reasons. RESULTS: At 6 months, similar numbers of events occurred in each group: 8 (placebo), 7 (low dose), and 8 (high dose), without deaths. Ventricular tachycardia responsive to amiodarone was more frequent in myoblast-treated patients: 1 (placebo), 3 (low dose), and 4 (high dose). A trend toward improvement in functional capacity was noted in myoblast-treated groups (Δ6-minute walk test of -3.6 vs +95.6 vs +85.5 m [placebo vs low dose vs high dose; P = .50]) without significant changes in Minnesota Living With HF scores. CONCLUSIONS: In HF patients with chronic postinfarction cardiomyopathy, transcatheter administration of myoblasts in doses of 400 to 800 million cells is feasible and may lead to important clinical benefits. Ventricular tachycardia may be provoked by myoblast injection but appears to be a transient and treatable problem. A large-scale outcome trial of myoblast administration in HF patients with postinfarction cardiomyopathy is feasible and warranted.