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Primary percutaneous coronary intervention (PCI) is now the recommended reperfusion technique for patients with acute ST-segment elevation myocardial infarction. However, despite early reperfusion in the majority of patients, PCI does not achieve effective myocardial reperfusion in a significant proportion of patients due to the prevalence of coronary microvascular obstruction. The amount of infarcted myocardium has been considered to be a reliable indicator of major adverse cardiovascular events and resultant adverse left ventricular remodeling. The purpose of this paper is to review the clinical benefits of supersaturated oxygen therapy following PCI for ST-segment elevation myocardial infarction.

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.

Introduction: Higher levels of low-density lipoprotein (LDL) are associated with an increased incidence of cardiovascular events. Little is known about the impact of lipid profile on the severity and extent of disease. This study aims to characterize the lipid profile’s ability to predict the number of and total length of coronary artery stents. Hypothesis: In patients undergoing percutaneous coronary intervention, the lipid panel is predictive of the total length and number of coronary stents deployed. Methods: We retrospectively identified unique, consecutive patients undergoing percutaneous coronary intervention at a single center from April 2018 to March 2021. Inclusion criteria included the availability of a lipid panel in the electronic medical record. Associations between lipid levels with stent number or stent length were tested by univariable linear regression. Results: For a single coronary angiogram procedure, 1547 unique patients had a lipid panel in the EMR within 2 weeks of the procedure with a median of 2 stents deployed with median total stent length of 38 mm. High-density lipoprotein (HDL), LDL, but not total cholesterol, triglycerides (TG), were predictive of stent length (HDL inversely, p =0.004; LDL p =0.01) and number of stents (HDL inversely, p =0.008; LDL p =0.04). Conclusions: These results indicate that the lipid panel has implications for the severity and extent of coronary artery disease found during coronary angiography, reflected in the number of and total length of coronary artery stents.

Load Haul Dump (LHD) equipment, haulers, and locomotives are essential to both hard and soft rock mining. Key performance indicators were calculated for both diesel and electric LHDs using the data...

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

Introduction: Cell therapy failed to improve global LV ejection fraction (LVEF) in most trials of post-MI LV dysfunction. LVEF does not consider the effect of cell therapy on different segments of the myocardium, which may be heterogeneous across different myocardial regions in patients with regional MI. Hypothesis: Allogeneic cardiosphere-derived cells (CDCs) improve segmental (but not global) myocardial function indexed as circumferential strain by MRI. Methods: In this randomized double-blind trial, 142 post-MI patients with LVEF Results: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3(10.8) and 108 (87.1%) males). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5%(4.0)) compared to placebo (0.2%(3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs. 0.04% (3.7) in the placebo group, p=0.04). The beneficial effect of CDCs for improving segmental Ecc was greater in patients with LV ejection fraction18.8% or LV end-diastolic volume index>100 [mixed effect regression coefficients of -0.92(p=0.02),-0.78(p=0.03), and -1.16(p=0.004) respectively versus -0.58(p=0.05) for the entire cohort]. Conclusions: In patients with post-MI LV dysfunction, allogeneic CDC administration resulted in improved segmental myocardial function. This CDC induced improvement in segmental myocardial function was greater in patients with severe LV dysfunction, dilated LV and greater infarct size. (clinicaltrials.gov Identifier: NCT01458405).

Myocardial free wall rupture is a rare but usually fatal complication of acute myocardial infarction (MI) especially if it occurs out of hospital and occurs in 2–4% of patients who suffer from acute MI. Rapid diagnosis is essential but not always easy as diagnostic tests may be inconclusive. In this case report authors examine a rare and unique patient survival after left ventricular free wall rupture following MI. The patient developed chest pain and hypotension in the hospital and was taken directly to the catheterization laboratory where a diagnostic angiogram showed a high-grade occlusion of a very small marginal branch, fluoroscopy demonstrated a large pericardial effusion, which was drained then auto transfused back to the patient using a femoral vein sheath. Rapid diagnostic testing including transesophageal echocardiography with Definity, transthoracic echocardiography, aortography and left ventriculography were all negative for dissection and rupture. Despite the negative diagnostic test, a high index of suspicion for rupture led to urgent surgical exploration where a large 4-cm hole was found in the lateral wall. Repair was successful and the patient left the hospital about several weeks later.

Background Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Mobilization of stem cells and homing within the infarcted area have been identified as the key mechanisms for successful treatment. Application of granulocyte-colony stimulating factor (G-CSF) is the least invasive way to mobilize stem cells while DDP4-inhibitor facilitates homing via stromal cell-derived factor 1 alpha (SDF-1α). Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. Purpose We initiated a phase II, multicenter, randomized, placebo-controlled efficacy and safety study (N=140) analyzing the effect of combined application of G-CSF and dutogliptin, a small molecule DPP-IV-inhibitor for subcutaneous use after acute myocardial infarction. Methods The primary objective of the study is to evaluate the safety and tolerability of dutogliptin (14 days) in combination with filgrastim (5 days) in patients with STEMI (EF 3.8% improvement in left ventricular ejection fraction (LV-EF). 140 subjects will be randomized to filgrastim plus dutogliptin or matching placebos. Results Baseline characteristics of the first 26 patients randomized (24 treated) in this trial reveal a majority of male patients (70.8%) and a medium age of 58.4 years (37 to 84). During the 2-week active treatment period, 35 adverse events occurred in 13 patients, with 4 rated as serious (hospitalization due to pneumonia N=3, hospitalization due to acute myocardial infarction N=1), and 1 adverse event was rated as severe (fatal pneumonia), 9 moderate, and 25 as mild. 6 adverse events were considered possibly related to the study medication, including cases of increased hepatic enzymes (N=3), nausea (N=1), subcutaneous node/suffusion (N=1) and syncope (N=1). Conclusions Our data demonstrate that the combined application of dutogliptin and G-CSF appears to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This research is funded by the sponsor RECARDIO, Inc., 1 Market Street San Francisco, CA 94150, USA. RECARDIO Inc. is funding the complete study. The Scientific Board of RECARDIO designed the study. Data Collection is at the participating sites. Interpretation of the data by the Scientific Board and Manuscript written by the authors and approved by the Sponsor

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.

LHD’s are expensive vehicles; therefore, it is important to accurately define the financial consequences associated with the investment of purchasing the mining equipment. This study concentrates on long-term incremental and sensitivity analysis to determine whether it is feasible to incorporate current battery technology into these machines. When revenue was taken into account, decreasing the amount of haulage in battery operated equipment by 5% or 200 kg per h amounts to a $4.0 × 104 loss of profit per year. On average it was found that using battery operated equipment generated $9.5 × 104 more in income annually, reducing the payback period from seven to two years to pay back the additional $1.0 × 105 investment of buying battery powered equipment over cheaper diesel equipment. Due to the estimated 5% increase in capital, it was observed that electric vehicles must possess a lifetime that is a minimum of one year longer than that of diesel equipment. Keywords: Sensitivity analysis, Underground mining vehicles, Battery power, Battery mining equipment, Economic evaluation

Esophagitis dissecans superficialis is a rare clinical endoscopic finding with poorly understood pathogenesis and ill-defined management. A 71-year-old man is admitted with progressively worsening dysphagia and odynophagia with endoscopic features most consistent with severe esophagitis dissecans superficialis. Extensive workup did not reveal an etiology, and he was subsequently treated with steroids, resulting in rapid, almost complete clinical and endoscopic recovery.

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 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.

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.

Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34 + cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34 + cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34 + administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34 + cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34 + ]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34 + Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)

I was pleased to see the thoughtful editorial by Dr. Chris White [(1)][1] in a recent issue of JACC: Cardiovascular Interventions . I remember the case Dr. White describes very well, and it reminded me of the many lessons we have learned about product development over the past 40 years. I also

Fibromyalgia (FM) has historically been associated with several diseases in gastroenterology and hepatology. The most substantiated evidence pertains to irritable bowel syndrome (IBS). The pathogeneses of FM and IBS remain unclear, but it is likely related to dysregulation within the brain-gut axis, resulting in a hyperalgesic state. IBS and FM share other similarities, including a female predominance, fatigue, insomnia, and susceptibility to psychiatric state. These common manifestations and pathogeneses serve as a foundation for overlapping, multidisciplinary treatment modalities.

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.

The history of coronary angioplasty began with the groundbreaking work of Andreas Gruntzig, who was the first to use balloon-expandable catheters for the treatment of flow-limiting atherosclerotic coronary artery lesions. Thereafter, early investigators tested self-expanding springs as a solution to abrupt closure and restenosis seen with balloon angioplasty but these devices suffered from difficult delivery and a high complication rate. Julio Palmaz and Richard Schatz introduced the first balloon-expandable stent as a mechanical support to improve vessel patency. Their pioneering work launched a new era in the treatment of coronary artery disease.

The high ionic strength and complex speciation of the anolyte solution within the CuCl(aq)/HCl(aq) electrolytic cell have impeded predictions of the energy requirements for the cell's electrolytic reaction at 25 °C and 1 bar. After collecting experimental open circuit potential (OCP) data and comparing the values obtained with predictions from prospective thermodynamic models, an approach to predict thermodynamic values and the overall efficiency was formulated. The compositions of the experimental measurements ranged from 2-2.5 mol of CuCl(aq) with 8-9 mol of HCl(aq) per kilogram of water in anolyte solution and 8-9 mol of HCl(aq) per kilogram of water in catholyte solution. From the OCP data, it was found that activity coefficient and speciation effects were critical in predicting the Gibbs energy, entropy and thermodynamic (intrinsic maximum) efficiency of the electrolytic cell. At equilibrium, all thermodynamic functions of the anolyte redox reactions were the same after activity coefficients and speciation effects were taken into account. The electrochemical reactions’ Gibbs energy and entropy were found to be 9700 J/mol and 2.18 J/(mol K) at 25 °C and 1 bar, which indicated that the reactions required a small amount of electrical and thermal energy to proceed. With thermodynamic values for the electrolytic reaction and experimental data from a CuCl(aq)/HCl(aq) electrolytic cell, the voltage, current, thermodynamic and overall efficiency were calculated. The overall efficiency ranged from 15 to 95% depending on the current density.

Sodium metal halide (NaMx) batteries are an emerging technology, with performance and longevity comparable to that of lithium ion (Li-ion) batteries, yet, require less capital. NaMx technology has been considered for mass transit and industrial applications to date. Mining vehicles are most commonly powered by diesel engines, despite their reputation for air pollution and inefficiency. These diesel powerhouses can be replaced by efficient, clean batteries while maintaining economic viability. In underground mining, locomotives and load-haul-dump are the most common light duty (

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a doubleblind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a “seamless” WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34

This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina.IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials.RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months.The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]).Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910).

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.

The field of myocardial regeneration (angiogenesis and myogenesis) might prove to play an important role in the future management of cardiovascular disease. Stem cells are currently undergoing testing in Phase I and Phase II clinical trials. Methods of delivery will affect the outcome of such therapies, perhaps significantly. This document provides suggested guidance in 4 methods of delivery: endocardial, intracoronary, coronary sinus, and epicardial.

Drug-eluting stents (DES) have had a profound impact on the practice of interventional cardiology. Important safety concerns regarding DES have been widely publicized and acknowledged. The primary emphasis has been placed on late stent thrombosis and the adverse sequela which result. Another emerging adverse effect of DES is coronary aneurysm (CAA) formation. We report on a patient who developed CAA formation after DES implantation but not at the site of previous bare-metal stent (BMS) implantation. We also review the current understanding of DES-associated CAA formation.

Aims The aim of this study was to determine whether platelet reactivity on clopidogrel therapy, as measured by a point-of-care platelet function assay, is associated with thrombotic events after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). Methods and results Platelet reactivity on clopidogrel (post-treatment reactivity) was measured with the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, CA, USA) in 380 patients undergoing PCI with sirolimus-eluting stents. Receiver-operating characteristic curve analysis was used to derive the optimal cut-off value for post-treatment reactivity in predicting 6 month out-of-hospital cardiovascular (CV) death, non-fatal MI, or stent thrombosis. The mean post-treatment reactivity was 184 ± 85 PRU (P2Y12 reaction units). The optimal cut-off for the combined endpoint was a post-treatment reactivity ≥235 PRU [area under the curve 0.711 (95% confidence interval 0.529–0.893), P = 0.03], which was similar to the threshold of the upper tertile (231 PRU). Patients with post-treatment reactivity greater than the cut-off value had significantly higher rates of CV death (2.8 vs. 0%, P = 0.04), stent thrombosis (4.6 vs. 0%, P = 0.004), and the combined endpoint (6.5 vs. 1.0%, P = 0.008). Conclusion High post-treatment platelet reactivity measured with a point-of-care platelet function assay is associated with post-discharge events after PCI with DES, including stent thrombosis. Investigation of alternative clopidogrel dosing regimens to reduce ischaemic events in high-risk patients identified by this assay is warranted.

We report two cases of an unusual accessory coronary artery arising from the left coronary cusp and traveling over the superior epicardial aspect of the left ventricle parallel to the left main coronary (LM) and the left anterior descending artery (LAD).

Splenic artery pseudoaneurysms are infrequently encountered but critical to recognize. Limited literature to date describes associations with pancreatitis, trauma, and rarely peptic ulcer disease. Hemorrhage and abdominal pain are the most common manifestations. There is typically overt gastrointestinal blood loss but bleeding can also extend into the peritoneum, retroperitoneum, adjacent organs, or even a pseudocyst. Most patients with ruptured splenic artery pseudoaneurysms present with hemodynamic instability. Here, we describe a patient recovering from acute illness in the intensive care unit but with otherwise no obvious risk factors or precipitants for visceral pseudoaneurysm. He presented with acute onset altered mental status, nausea, and worsening back and abdominal pain and was found to be in hypovolemic shock. The patient was urgently stabilized until more detailed imaging could be performed, which ultimately revealed the source of blood loss and explained his rapid decompensation. He was successfully treated with arterial coiling and embolization. Thus, we herein emphasize the importance of prompt recognition of hemorrhagic shock and of aggressive hemodynamic stabilization, as well as a focused diagnostic approach to this problem with specific treatment for splenic artery pseudoaneurysm. Finally, we recommend that multidisciplinary management should be the standard approach in all patients with splenic artery pseudoaneurysm.

The optimal treatment for sirolimus-eluting stent (SES) restenosis is not known. This study evaluated the safety and clinical outcome of paclitaxel-eluting stent (PES) implantation for SES restenosis. From March 2004 to July 2005, PESs were implanted in 125 patients with 140 lesions with SES restenosis. Acute and 6-month clinical outcomes were determined through review of the medical record and/or telephone interview. In-hospital major adverse cardiac events (death, nonfatal myocardial infarction, or repeat revascularization) occurred in 14 patients (11.2%), driven entirely by postprocedure non-Q-wave myocardial infarction. At a mean clinical follow-up of 7.2 +/- 1.8 months, the incidence of target lesion revascularization (TLR) was 14.0%, and the rate of major adverse cardiac events was 17.2%. Subacute thrombosis occurred in 2 patients (1.6%). Length of PES implanted, postprocedure diameter stenosis, and total occlusion of the target lesion were independent predictors of TLR. In patients with de novo SES restenosis, TLR was only 8.7%. In conclusion, at medium-term follow-up, PES implantation for SES failure appears to be safe and effective, although efficacy is decreased in the setting of total occlusions, greater residual diameter stenosis, and longer PESs.

The purpose of this study was to evaluate the clinical outcome of patients undergoing sirolimus-eluting stent implantation for de novo lesions within saphenous vein grafts (SVGs). Although the incidence of restenosis following sirolimus-eluting stenting (SES) of native coronary arteries is low, the efficacy of SES to treat de novo lesions within SVGs has not been well studied. A total of 35 patients underwent SES implantation of 39 lesions during 36 procedures. All patients had a minimum follow-up of 6 months following the index procedure. The mean bypass graft age was 10.1 +/- 6.5 years (range, 0-23 years). In-hospital major adverse cardiac events [death, myocardial infarction, thrombosis, or target vessel revascularization (TVR)] occurred in four patients (11%). Clinical follow-up was obtained in 100% of patients (mean follow-up, 7.5 +/- 2.2 months). There was one cardiac death, presumed due to stent thrombosis. TVR occurred in only two patients (6%). Myocardial infarction (MI) occurred in four patients (11%), all attributable to a nontarget vessel. The combined endpoint of death, MI, or TVR occurred in seven patients (20%). Freedom from death, nonfatal MI, thrombosis, or any revascularization was 65%. Early experience indicates sirolimus-eluting stents for de novo saphenous vein graft lesions have a low (6%) rate of clinically driven target vessel revascularization. By 7-month follow-up, event-free survival is limited primarily by disease in nontarget vessels.

Background: The short-term clinical impact of intramyocardial gene transfer (GT) of the angiogenic protein vascular endothelial growth factor-2 (VEGF-2) has been previously reported to significantly reduce Canadian Cardiovascular Society (CCS) angina class and to prolong exercise treadmill test (ETT) time. We describe the safety and long-term events (>1 year) in consecutive, nonrandomized, patients who received intramyocardial VEGF-2. Methods: Thirty patients with intractable CCS class III or IV angina and no options for revascularization underwent direct intramyocardial GT of VEGF-2 naked DNA via limited thoracotomy at total doses of 0.2, 0.8, or 2.0 mg. Patients were followed for clinical events after 1 year by hospital records, follow-up visits or telephone contact. Due to one perioperative death, 29 patients were followed. Results: At a mean follow-up of 751 ± 102.5 days (range 459–959) there were four deaths (13.8%), five myocardial infarctions (MIs) (17.2%), and seven revascularization procedures (24.1%). There were 15 hospitalizations in 12 patients. At the end of the follow-up period no patient (0%) had CCS class IV angina, 3 patients (11.5%) had class III angina, and 23 (88.5%) had class I to II angina. There were two new diagnoses of cancer. Conclusion: Transthoracic intramyocardial injection of VEGF-2 is associated with an improvement of symptoms of angina in the majority of patients beyond the first year of treatment. Major clinical events such as death, MI, and repeat revascularization are uncommon during the first year but more frequent after 1 year at a rate consistent with the severity of underlying disease in this population with advanced atherosclerosis. The majority of events were the result of progression of disease in areas of the heart remote from the site of GT. A large randomized trial is planned to determine the efficacy of intramyocardial VEGF-2 injections in inoperable patients.

Phase I, II and prematurely terminated phase III trials of autologous CD34+ cell therapy provide consistent evidence for improving exercise time and trends towards reductions in mortality, but these studies were not individually powered to define efficacy. Exercise times were estimated across the

This phase I open label, dose-escalating study shows that gene transfer of vascular endothelial growth factor-2 naked deoxyribonucleic acid by direct myocardial injection by way of thoracotomy in patients with Canadian Cardiovascular Society class 3 or 4 angina is feasible and safe. The procedure is well tolerated, with few major adverse cardiac events at 1 year, and without complications directly related to gene expression. In this prospective, nonblinded study, the procedure is associated with clinical improvement; however, there was no angiographic evidence of angiogenesis and there is a great potential for a sham or placebo effect in the study patients. A randomized phase III trial is underway that will help determine the efficacy of vascular endothelial growth factor-2 gene transfer in “no-option” patients.

Background — Several clinical trials indicate that intracoronary radiation is safe and effective for treatment of restenotic coronary arteries. We previously reported 6-month and 3-year clinical and angiographic follow-up demonstrating significant decreases in target lesion revascularization (TLR) and angiographic restenosis after γ radiation of restenotic lesions. The objective of this study was to document the clinical outcome 5 years after treatment of restenotic coronary arteries with catheter-based iridium-192 ( 192 Ir). Methods and Results — A double-blind, randomized trail compared 192 Ir to placebo sources in patients with restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to 192 Ir and 29 to placebo. At 5-year follow-up, TLR was significantly lower in the 192 Ir group (23.1% versus 48.3%; P =0.05). There were 2 TLRs between years 3 and 5 in patients in the 192 Ir group and none in patients in the placebo group. The 5-year event-free survival rate (freedom from death, myocardial infarction, or TLR) was greater in 192 Ir-treated patients (61.5% versus 34.5%; P =0.02). Conclusions — Despite apparent mitigation of efficacy over time, there remains a significant reduction in TLR at 5 years and an improvement in event-free survival in patients treated with intracoronary 192 Ir. The early clinical benefits after intracoronary γ radiation with 192 Ir seem durable at 5-year clinical follow-up.

Background: Diabetic patients undergoing coronary interventional procedures are at increased risk of restenosis and adverse clinical events. The relative impact of stents compared with balloon angioplasty on the outcome of percutaneous intervention in diabetics remains controversial. Hypothesis: The goal of this study was to determine whether stent placement was superior to balloon angioplasty in reducing restenosis of diabetic patients undergoing coronary intervention. Methods: The STRESS Trial was a prospective randomized comparison of stent placement and balloon angioplasty in the treatment of new native coronary lesions. Of 594 randomized patients, 92 (16%) were diabetic. In this substudy analysis of the STRESS Trial, the outcomes after stenting and balloon angioplasty in diabetic patients were compared. The primary endpoint was restenosis as determined by angiography at 6 months. Clinical outcomes at 1 year were assessed. Results: Procedural success was achieved in 82% of diabetic patients assigned to angioplasty and in 100% assigned to stenting (p

Background — This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina. Methods and Results — A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61±2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 μg (n=9), 800 μg (n=9), or 2000 μg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (−1.3 versus −0.1, P =0.04). Remaining efficacy end points—including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by ≥2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data—all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment. Conclusions — This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.

Introduction: In CADUCEUS, autologous cardiosphere-derived cells decreased infarct size and increased viable tissue in post-myocardial infarction (MI) subject s. Hypothesis: The first-in-human Phase I ALLSTAR trial was designed to test the safety and feasibility of intracoronary infusion of allogeneic cardiosphere-derived cells (CAP-1002) in patients with an anterior MI, within the prior 12 months with a scar size >15% by Magnetic Resonance Imaging (MRI). Methods: A total of 14 adult subjects (mean age = 55.6 yr; range 40-66 years) with a recent (28 - 90 days; n=9) or chronic (91-365 days; n=5) anterior MI (mean infarct size 25.4%; range 15.3% - 32.7%) and LV dysfunction (mean LVEF 42%; range 26.7% - 55.1%) were prospectively enrolled and infused with CAP-1002 (n=4 at 12.5M dose; n=10 at 25M dose) via stop-flow intracoronary infusion. Primary safety endpoints were: MACE events (recurrent MI, hospitalization or ER treatment for heart failure, Left Ventricular Assist Device placement or heart transplantation), acute myocarditis, death due to arrhythmias or unwitnessed death. Humoral and cellular immunologic responses were assessed via single antigen bead and ELISpot assays. Results: No pre-specified safety endpoint occurred. Only two adverse events were treatment-related, both transient hypotension related to nitroglycerin. There were no clinically significant rises in peri-procedural cardiac enzymes. Donor specific antibodies (DSAs) were present in four subjects prior to infusion; one resolved and three presistent at 6 months of follow up. De novo DSA’s developed in four subjects, three resolved during follow up and one persisted at 6 months of follow up. All DSA levels were low (MFI Conclusions: Intracoronary infusion of allogeneic cardiosphere-derived cells (CAP-1002) appears to be safe and feasible. On the basis of the Phase 1 findings, the ALLSTAR trial has proceeded to a Phase II randomized, double-blind trial, powered to assess reduction of scar size by MRI.