Objectives Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Background Bone ...marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. Methods We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Results Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p = 0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p = 0.003) in the hMSC-treated patients. Global symptom score in all patients (p = 0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Conclusions Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells MSC to Treat Acute Myocardial Infarction; NCT00114452 )
Atrial fibrillation (AF) is mediated by oxidative stress, neurohormonal activation, and inflammatory activation. Serum uric acid (SUA) is a surrogate marker of oxidative stress. Xanthine oxidase ...produces SUA and is upregulated by inflammation and neurohormones.
To perform a meta-analysis to evaluate the evidence supporting an association between AF and SUA.
We searched the MEDLINE database (1966 to 2013) supplemented by manual searches of bibliographies of key relevant articles. We selected all cross-sectional and cohort studies in which SUA was measured and AF was reported. In cross-sectional studies, we calculated the pooled standardized mean difference of SUA between those with AF and those without AF. In cohort studies, we calculated the pooled relative risk with the corresponding 95% confidence interval (CI) for incident AF by using the random effects method.
The search strategy yielded 40 studies, of which only 9 met our eligibility criteria. The 6 cross-sectional studies comprised 7930 evaluable patients with a median prevalence of heart failure of 4% (IQR 0%-100%). The standardized mean difference of SUA for those with AF was 0.42 (95% CI 0.27-0.58) compared with those without AF. The 3 cohort studies evaluated 138,306 individuals without AF. The relative risk of having AF for those with high SUA was 1.67 (95% CI 1.23-2.27) compared with those with normal SUA.
High SUA is associated with AF in both cross-sectional and cohort studies. It is unclear whether SUA represents a disease marker or a treatment target.
Abstract Background Both bone marrow–derived mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using ...xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. Objectives To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. Methods Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. Results Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs −44.1 ± 6.8%; CSC/MSC −37.2 ± 5.4%; placebo −12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. Conclusions These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.
Although there is tremendous interest in stem cell (SC)–based therapies for cardiomyopathy caused by chronic myocardial infarction, many unanswered questions regarding the best approach remain. The ...TAC-HFT study is a phase I/II randomized, double-blind, placebo-controlled trial designed to address several of these questions, including the optimal cell type, delivery technique, and population. This trial compares autologous mesenchymal SCs (MSCs) and whole bone marrow mononuclear cells (BMCs). In addition, the study will use a novel helical catheter to deliver cells transendocardially. Although most trials have used intracoronary delivery, the optimal method is unknown and data suggest that the transendocardial approach may have important advantages. Several trials support the benefit of SCs in patients with chronic ischemic cardiomyopathy (ICMP), although the sample sizes have been small and the number of trials sparse. After a pilot phase of 8 patients, 60 patients with ICMP (left ventricular ejection fraction 15%-50%) will be randomized to group A (30 patients further randomized to receive MSC injection or placebo in a 2:1 fashion) or group B (30 patients further randomized to BMCs or placebo in a 2:1 fashion). All patients will undergo bone marrow aspiration and transendocardial injection of SCs or placebo. The primary and secondary objectives are, respectively, to demonstrate the safety and efficacy (determined primarily by cardiac magnetic resonance imaging) of BMCs and MSCs administered transendocardially in patients with ICMP.
Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We ...conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.
Abstract Background The role of patient age in the efficacy of mesenchymal stem cell (MSC) therapy in ischemic cardiomyopathy (ICM) is controversial. Objectives This study sought to determine whether ...the therapeutic effect of culture-expanded MSCs persists, even in older subjects. Methods Patients with ICM who received MSCs via transendocardial stem cell injection (TESI) as part of the TAC-HFT (Transendocardial Autologous Cells in Ischemic Heart Failure) (n = 19) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis) (n = 30) clinical trials were divided into 2 age groups: younger than 60 and 60 years of age and older. Functional capacity was measured by 6-min walk distance (6MWD) and quality of life using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score, measured at baseline, 6 months, and 1 year post-TESI. Various cardiac imaging parameters, including absolute scar size, were compared at baseline and 1 year post-TESI. Results The mean 6MWD was similar at baseline and increased at 1 year post-TESI in both groups: 48.5 ± 14.6 m (p = 0.001) for the younger and 35.9 ± 18.3 m (p = 0.038) for the older participants (p = NS between groups). The older group exhibited a significant reduction in MLHFQ score (−7.04 ± 3.54; p = 0.022), whereas the younger than 60 age group had a borderline significant reduction (−11.22 ± 5.24; p = 0.058) from baseline (p = NS between groups). Although there were significant reductions in absolute scar size from baseline to 1 year post-TESI, the effect did not differ by age. Conclusions MSC therapy with TESI in ICM patients improves 6MWD and MLHFQ score and reduces myocardial infarction size. Importantly, older individuals did not have an impaired response to MSC therapy.
Abstract Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem ...cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+ ; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.
Impact of Oxypurinol in Patients With Symptomatic Heart Failure: Results of the OPT-CHF Study Joshua M. Hare, Brian Mangal, Joanne Brown, Charles Fisher Jr, Ronald Freudenberger, Wilson S. Colucci, ...Douglas L. Mann, Peter Liu, Michael M. Givertz, Richard P. Schwarz, for the OPT-CHF FAILURE Investigators This study evaluated if xanthine oxidase (XO) inhibition with oxypurinol (600 mg per day) produces clinical benefits in optimally treated, symptomatic patients (n = 405) with heart failure (HF) and systolic dysfunction. Oxypurinol did not affect a composite clinical end point comprising morbidity, mortality, and quality of life in the total patient population at 6 months. Post-hoc analysis suggested benefits occur in patients with elevated serum uric acid (SUA) correlating with SUA reduction. This study failed to support the efficacy of oxypurinol in this patient population but suggests that SUA may serve as a valuable biomarker to target XO inhibition in HF.
Abstract Background While human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic non-ischemic dilated cardiomyopathy (NIDCM). Objectives The ...POSEIDON-DCM trial is a randomized comparison of safety and efficacy of autologous (auto) vs. allogeneic (allo) bone marrow-derived hMSCs in NIDCM. Methods Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients (age: 55.8 + 11.2; 32% female) received hMSCs (100 million) by transendocardial stem cell injection (TESI) in ten left ventricular sites by NOGA Catheter. Treated patients were evaluated at baseline, 30 days, 3-, 6-, and 12-months for safety: serious adverse events (SAE), and efficacy endpoints: Ejection Fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Six Minute Walk Test (6MWT), MACE, and immune-biomarkers. This trial is registered with ClinicalTrials.gov , #NCT01392625. Results There were no 30-day treatment-emergent (TE)-SAEs. 12-month SAE incidence was 28.2% (95% CI: 12.8, 55.1) in allo, and 63.5% (95% CI: 40.8, 85.7; p=0.1004) in auto. One allo-group patient developed an elevated donor specific cPRA. EF increased in allo by 8.0 units (95% Cl: 2.8, 13.2; p=0.004), and in auto: 5.4 units (95% Cl: -1.4, 12.1; p=0.116, allo vs. auto p=0.4887). 6MWT increased for allo: 37.0 meters (95% Cl: 2.0 to 72.0; p=0.04), but not auto: 7.3 meters (95% Cl: -47.8, 33.3; p=0.71, auto vs. allo p=0.0168). MLHFQ score decreased in allo (p=0.0022), and auto (p=0.463; p=0.172). The MACE rate was lower in allo vs. auto (p=0.0186). Tumor necrosis factor alpha (TNF-α) decreased (p=0.0001 for each), to a greater extent in allo vs. auto at six-months (p=0.05). Conclusion These findings demonstrate safety and support greater, clinically meaningful efficacy of allo-hMSC vs. auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results.
Epicardial fat assessed using echocardiography is associated with abdominal visceral adipose tissue and cardiovascular risk factors. Because of its location, epicardial fat may directly affect the ...coronary vasculature and myocardium through local secretion of bioactive molecules. This study examines the effects of weight loss after bariatric surgery on epicardial adipose tissue in patients with severe obesity. Clinical data and echocardiograms of 23 patients with severe obesity who had echocardiograms recorded before and 8.3 ± 3.7 months after undergoing bariatric surgery were retrospectively reviewed. Epicardial fat thickness was measured as the hypoechoic space anterior to the right ventricle in both the parasternal long- and short-axis views, and an average was obtained. At baseline, patients had increased epicardial fat compared with normal-weight controls matched for age, gender, and ethnicity (5.3 ± 2.4 vs 3.0 ± 1.1 mm, p <0. 001). Epicardial fat thickness was associated with the patient’s initial weight in severely obese patients (r = 0.51, p = 0.011). Patients lost an average of 40 ± 14 kg after surgery. Epicardial fat thickness decreased from 5.3 ± 2.4 to 4.0 ±1.6 mm (p = 0.001). Change in epicardial fat correlated with initial epicardial fat thickness measured using echocardiography (r = 0.71, p <0.001). In conclusion, epicardial fat thickness decreases in severely obese patients who have substantial weight loss after bariatric surgery. Measuring epicardial fat thickness using echocardiography may be useful to monitor visceral fat loss with weight reduction therapies.
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