Therapy For Ischemic Heart Disease Research Articles

ANTIARRHYTHMIC ACTION OF CARDIOCYTOPROTECTORS IN TREATMENT OF ISCHEMIC HEART DISEASE WITH VENTRICULAR ARRHYTHMIAS

It is known that ventricular dysrhythmias in patients with ischemic heart diasease can be of various origin. Hence selection of antiarrhythmic tactics in such patients should be individual and pathogenetically proved. Aim. To check antiarrhythmic abilities of metabolic therapy for ischemic heart disease combined with variety of ventricular arrhythmias of III-IV grades (by Myerburg RJ). Material and methods. for 42 patients with ventricular arrhythmias of high grade and stable ischemic heart disease with saved ejection fraction of the left ventricle, before and after treatment were done the following: Holter monitoring, treadmill test, and as indicated — coronary arteriography, radionuclide methods of perfusion assessment and metabolism of myocardium, non-invasive topical diagnostics. To individually selected antianginal and antihypertension therapy for all patients was added ethylmethylhydroxypyridine succinate (es) in daily dosage 300 mg, for 2 months. Results. During the study, according to relationship of ventricular arrhythmia with transient ischemia, patients were selected to 2 groups. In the 1 group, with ischemic arrhythmias, in 2 months after start of es, there was significant antiarrhythmic effect: number of single ventricular premature beats decreased by 55%, couplets — by 90%, and episodes of non-sustained ventricular tachicardia — by 100%. At control positrone-emisson tomography in the areas of myocardial ischemia there was significant increase of 11C-buthirate sodium excretion, which witness on the increase of efficacy of energetic metabolism in zones of hypoxia. In the II group, with non-ischemic ventricular arrhythmias — antiarrhythmic effect was not achieved. Conclusion. es should be regarded as pathogenetic chain in complex antiarrhythmic treatment of ventricular arrhythmias in patients with stable ischemic heart disease.

Stem Cell Therapy of Ischemic Heart Disease

Ischemic heart disease (IHD) accelerates death of cardiomyocytes and leads to the onset of cardiac failure. Due to the application of stem cells, there exists a potential for the regeneration of a damaged myocardium. Here we present a brief review of the modern data on the application of various types of stem cells for the IHD therapy. We consider different types of stem cells, which are most preferable for the clinical application, including mesenchymal stem cells, cardiac stem cells, embryonic stem cells, iPS cells and others. In particular, we discuss their advantages and strategies which can be applied in order to boost their regenerative potential, as well as optimization of their delivery. Besides, our review refers to the contemporary achievements in the field of tissue engineering of heart, using both polymer scaffolds and scaffold-free constructs. We also discuss the most prominent known clinical trials on stem cell therapy of ischemic heart disease.

Melatonin facilitates adipose-derived mesenchymal stem cells to repair the murine infarcted heart via the SIRT1 signaling pathway.

Mesenchymal stem cells (MSCs)-based therapy provides a promising therapy for the ischemic heart disease (IHD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment, characterized by excessive inflammation and oxidative stress in the host's infarcted myocardium. Melatonin, an indole, which is produced by many organs including pineal gland, has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Using a murine model of myocardial infarction (MI), this study was designed to evaluate the impact of melatonin on adipose-derived mesenchymal stem cells (AD-MSCs)-based therapy for MI and the underlying mechanism involved with a focus on silent information regulator 1(SIRT1) signaling. Our results demonstrated that melatonin promoted functional survival of AD-MSCs in infarcted heart and provoked a synergetic effect with AD-MSCs to restore heart function. This in vivo effect of melatonin was associated with alleviated inflammation, apoptosis, and oxidative stress in infarcted heart. In vitro studies revealed that melatonin exert cytoprotective effects on AD-MSCs against hypoxia/serum deprivation (H/SD) injury via attenuating inflammation, apoptosis, and oxidative stress. Mechanistically, melatonin enhanced SIRT1 signaling, which was accompanied with the increased expression of anti-apoptotic protein Bcl2, and decreased the expression of Ac-FoxO1, Ac-p53, Ac-NF-ΚB, and Bax. Taken together, our findings indicated that melatonin facilitated AD-MSCs-based therapy in MI, possibly through promoting survival of AD-MSCs via SIRT1 signaling. Our data support the promise of melatonin as a novel strategy to improve MSC-based therapy for IHD, possibly through SIRT1 signaling evocation.

Cardiac Usage of Reducible Poly(oligo-D-arginine) As a Gene Carrier for Vascular Endothelial Growth Factor Expression.

Developments of non-viral carriers have headed toward reducing cytotoxicity, which results from the use of conventional gene carriers, and enhancing gene delivery efficiency. Cys-(d-R9)-Cys repeated reducible poly(oligo-D-arginine) (rPOA) is one of the most efficient non-viral carriers for gene therapy; however, while its efficiency has been verified in the lung and brain, it is necessary to confirm its activity in each organ or tissue since there are differences of gene carrier susceptibility to among tissue types. We therefore tested the compatibility of rPOA in cardiac tissue by in vitro or in vivo experiments and confirmed its high transfection efficiency and low cytotoxicity. Moreover, substantial regenerative effects were observed following transfection with rPOA/pVEGF expression vector complexes (79% decreased infarct size) compared to polyethyleneimine (PEI) (34% decreased infarct size) in a rat myocardial infarction (MI) model. These findings suggest that rPOA efficiently enables DNA transfection in cardiac tissue and can be used as a useful non-viral therapeutic gene carrier for gene therapy in ischemic heart disease.

Abstract 16655: Bone Marrow Cell Therapy in Patients With Ischemic Heart Disease: A Meta-analysis of Randomized Controlled Trials Using Cardiac MRI

Introduction: The results from clinical trials of bone marrow cell (BMC) therapy in ischemic heart disease (IHD) have been discordant with regard to left ventricular (LV) functional improvement. This discrepancy has been attributed, in part, to the use of dissimilar cardiac imaging modalities. MRI is the gold standard for assessment of cardiac structure/function. Hypothesis: We hypothesized that BMC therapy will improve LV parameters in patients with IHD when assessed by cardiac MRI. Methods: We performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) of BMC therapy in patients with IHD that used cardiac MRI. Database searches through May 30, 2015 identified 27 eligible RCTs (enrolling 1826 patients). The MRI data on LV ejection fraction (EF), infarct size, LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV) were analyzed with random-effects meta-analysis. Clinical outcomes were analyzed using Peto odds ratio (OR). Results: Compared with standard therapy, BMC therapy improved LVEF (1.62%; 95% confidence interval [CI]: 0.49 to 2.75; P=0.005) and reduced LVESV (-2.00 ml; 95% CI: -3.19 to -0.82; P=0.0009). The improvement in LVEF was similar in patients with acute myocardial infarction (MI) and chronic IHD. Perhaps more importantly, BMC therapy was associated with reduced incidence of recurrent MI (OR: 0.39; 95% CI: 0.20 to 0.78; P=0.007) along with substantial improvement in other outcome parameters, including mortality (Table). However, these changes did not reach statistical significance perhaps due to smaller patient numbers. Conclusions: These results from meta-analysis of RCTs using cardiac MRI indicate that BMC therapy improves LV function and outcomes in patients with IHD. These data may help resolve the controversy regarding whether the reported benefits of BMC therapy are dependent on the selection of imaging modalities.

Abstract 15100: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS

Introduction: Iron can catalyze the formation of reactive oxygen species (ROS) and promote tissue damage. While some studies suggested benefits with iron chelation therapy in ischemic heart disease (IHD), several others failed to show any benefits. Mitochondria are a major site of iron utilization and ROS production, and mitochondrial iron accumulation has been associated with increased oxidative stress. We therefore hypothesized that mitochondrial iron plays a causative role in ischemia/reperfusion (I/R) damage, and a decrease in mitochondrial iron (as opposed to cytoplasmic iron) would be sufficient to protect against I/R injury. Results: We observed an increase in cardiac mitochondrial iron in mice after I/R injury. Using two iron chelators with distinct mitochondrial permeability, i.e., 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that does not modulate mitochondrial iron), we demonstrated that mice pretreated with BPD but not DFO were protected against I/R injury. Similar results were obtained in vitro . Since these two iron chelators also modulate iron in other subcellular compartments, we used transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 to confirm that modulation of mitochondrial iron alone is sufficient to confer protection. ABCB8 TG mice had significantly lower mitochondrial iron (but normal cytosolic iron) in the heart compared to nontransgenic (NTG) littermates at baseline, but exhibited normal cardiac function. After I/R, ABCB8 TG mice displayed significantly less apoptosis and lower levels of markers of ROS and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury, most likely through a reduction in ROS. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is sufficient to protect against I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for the treatment of IHD.

Новые аспекты клеточной терапии ишемических заболеваний сердца (обзор литературы)

The authors reviewed the modern methods of cell therapy for ischemic heart disease. The experimental and clinical researches demonstrated that transplantation of hematopoietic progenitor cells and mesenchymal stem cells contributes to reduction of the postinfarction scar size, to increase of left ventricular ejection fraction, to decrease of cardiac remodeling, resulting in the reduction of end-diastolic and end-systolic volumes. This treatment promoted an increase of exercise tolerance, decrease of angina functional class and improved the quality of life. The best long-term results were observed for the early beginning of cell therapy and the implantation of cells directly into the myocardium. The cultures of resident cardiomyocyte progenitor cells significantly improved the results of treatment. Hypoxic preconditioning or low intensity laser irradiation enhanced the therapeutic potential of the cells cultured for transplantation, activated proliferation and reduced apoptosis. Good results were achieved with laser revascularization of myocardium before the cell transplantation. New non-invasive methods of treatment for ischemic heart disease, based on the increase in the concentration of stem cells in peripheral blood with G-CSF application or laser irradiation of the bone marrow localization areas were suggested.

Demographic and Prescribing Patterns of Chinese Herbal Products for Individualized Therapy for Ischemic Heart Disease in Taiwan: Population-Based Study.

ObjectiveCombinations of Chinese herbal products (CHPs) are widely used for ischemic heart disease (IHD) in Taiwan. We analyzed the usage and frequency of CHPs prescribed for patients with IHD.MethodsA nationwide population-based cross-sectional study was conducted, 53531 patients from a random sample of one million in the National Health Insurance Research Database (NHIRD) from 2000 to 2010 were enrolled. Descriptive statistics, the multiple logistic regression method and Poisson regression analysis were employed to estimate the adjusted odds ratios (aORs) and adjusted risk ratios (aRRs) for utilization of CHPs.ResultsThe mean age of traditional Chinese medicine (TCM) nonusers was significantly higher than that of TCM users. Zhi-Gan-Cao-Tang (24.85%) was the most commonly prescribed formula CHPs, followed by Xue-Fu-Zhu-Yu-Tang (16.53%) and Sheng-Mai-San (16.00%). The most commonly prescribed single CHPs were Dan Shen (29.30%), Yu Jin (7.44%), and Ge Gen (6.03%). After multivariate adjustment, patients with IHD younger than 29 years had 2.62 times higher odds to use TCM than those 60 years or older. Residents living in Central Taiwan, having hyperlipidemia or cardiac dysrhythmias also have higher odds to use TCM. On the contrary, those who were males, who had diabetes mellitus (DM), hypertension, stroke, myocardial infarction (MI) were less likely to use TCM.ConclusionsZhi-Gan-Cao-Tang and Dan Shen are the most commonly prescribed CHPs for IHD in Taiwan. Our results should be taken into account by physicians when devising individualized therapy for IHD. Further large-scale, randomized clinical trials are warranted in order to determine the effectiveness and safety of these herbal medicines.

Injectable shear-thinning hydrogels used to deliver endothelial progenitor cells, enhance cell engraftment, and improve ischemic myocardium

ObjectivesThe clinical translation of cell-based therapies for ischemic heart disease has been limited because of low cell retention (<1%) within, and poor targeting to, ischemic myocardium. To address these issues, we developed an injectable hyaluronic acid (HA) shear-thinning hydrogel (STG) and endothelial progenitor cell (EPC) construct (STG-EPC). The STG assembles as a result of interactions of adamantine- and β-cyclodextrin–modified HA. It is shear-thinning to permit delivery via a syringe, and self-heals upon injection within the ischemic myocardium. This directed therapy to the ischemic myocardial border zone enables direct cell delivery to address adverse remodeling after myocardial infarction. We hypothesize that this system will enhance vasculogenesis to improve myocardial stabilization in the context of a clinically translatable therapy. MethodsEndothelial progenitor cells (DiLDL+ VEGFR2+ CD34+) were harvested from adult male rats, cultured, and suspended in the STG. In vitro viability was quantified using a live-dead stain of EPCs. The STG-EPC constructs were injected at the border zone of ischemic rat myocardium after acute myocardial infarction (left anterior descending coronary artery ligation). The migration of the enhanced green fluorescent proteins from the construct to ischemic myocardium was analyzed using fluorescent microscopy. Vasculogenesis, myocardial remodeling, and hemodynamic function were analyzed in 4 groups: control (phosphate buffered saline injection); intramyocardial injection of EPCs alone; injection of the STG alone; and treatment with the STG-EPC construct. Hemodynamics and ventricular geometry were quantified using echocardiography and Doppler flow analysis. ResultsEndothelial progenitor cells demonstrated viability within the STG. A marked increase in EPC engraftment was observed 1-week postinjection within the treated myocardium with gel delivery, compared with EPC injection alone (17.2 ± 0.8 cells per high power field (HPF) vs 3.5 cells ± 1.3 cells per HPF, P = .0002). A statistically significant increase in vasculogenesis was noted with the STG-EPC construct (15.3 ± 5.8 vessels per HPF), compared with the control (P < .0001), EPC (P < .0001), and STG (P < .0001) groups. Statistically significant improvements in ventricular function, scar fraction, and geometry were noted after STG-EPC treatment compared with the control. ConclusionsA novel injectable shear-thinning HA hydrogel seeded with EPCs enhanced cell retention and vasculogenesis after delivery to ischemic myocardium. This therapy limited adverse myocardial remodeling while preserving contractility.

Stem Cell Therapy for Myocardial Infarction 2001-2013 Revisited.

Stem cell therapy for ischemic heart disease was an emerging concept in the early 2000s. First hopes were largely overshadowed by rather inconsistent results in human trials conducted in the middle of the decade. We aimed at investigating how the field of stem cell research expanded worldwide over the years using scientometric methods. We performed a PubMed inquiry and screened a total of 2609 publications dealing with stem cell therapy for myocardial infarction in the years 2001-2013. Density equalizing maps were used to visualize important centres of stem cell research worldwide. This systematic bibliometric study revealed an increasing research interest in the field of stem cell research in the context of ischemic heart disease over the last decade. Though some of the large human trials failed to show significant effects of stem cell therapy, especially basic science represents an ever growing field that evolved promising new concepts over the last couple of years. The scientific principle of protective paracrine mediators released from transplanted stem cells seems to bear great potential for future cell-free therapeutic use. However, further mechanistic insights are needed before transition from bench to bedside should be attempted, taking the lessons learned from previous studies into account.

Cardioprotective effects on ischemic myocardium induced by SVVYGLR peptide via its angiogenic-promoting activity

In ischemic heart disease, cardiomyocyte death results from both necrosis and apoptosis, and the area of infarction gradually increases. The induction of therapeutic angiogenesis is a promising therapy for this condition. In the present study, we investigated the actions of SV peptide—a 7-amino-acid sequence with angiogenic properties derived from osteopontin in the extracellular matrix—in a rat model of myocardial ischemia. We examined the angiogenesis activity of SV ex vivo using ring assay and dorsal air sac assay and in ischemic myocardium. We also conducted histological evaluations of left-ventricle remodeling and evaluated left ventricular (LV) function by echocardiography. The SV peptide had strong angiogenic effects both ex vivo and in vivo. In the experimental rats, this peptide stimulated the formation of new blood vessels in ischemic myocardium. Histological evaluation of the left ventricle in the SV-treated group showed a significant decrease in the size of the infarction, rate of myocardial fibrosis, and cardiomyocyte hypertrophy. Moreover, administration of the SV peptide significantly improved LV function. These results indicate that SV peptide induced angiogenesis in ischemic myocardium and improved cardiac function. Thus, it could serve as a potentially useful new therapy for ischemic heart disease.

Equilibrative Nucleoside Transporters 1 and 4: Which One Is a Better Target for Cardioprotection Against Ischemia-Reperfusion Injury?

:The cardioprotective effects of adenosine and adenosine receptor agonists have been studied extensively. However, their therapeutic outcomes in ischemic heart disease are limited by systemic side effects such as hypotension, bradycardia, and sedation. Equilibrative nucleoside transporter (ENT) inhibitors may be an alternative. By reducing the uptake of extracellular adenosine, ENT1 inhibitors potentiate the cardioprotective effect of endogenous adenosine. They have fewer systemic side effects because they selectively increase the extracellular adenosine levels in ischemic tissues undergoing accelerated adenosine formation. Nonetheless, long-term inhibition of ENT1 may adversely affect tissues that have low capacity for de novo nucleotide biosynthesis. ENT1 inhibitors may also affect the cellular transport, and hence the efficacy, of anticancer and antiviral nucleoside analogs used in chemotherapy. It has been proposed that ENT4 may also contribute to the regulation of extracellular adenosine in the heart, especially under the acidotic conditions associated with ischemia. Like ENT1 inhibitors, ENT4 inhibitors should work specifically on ischemic tissues. Theoretically, ENT4 inhibitors do not affect tissues that rely on ENT1 for de novo nucleotide synthesis. They also have no interaction with anticancer and antiviral nucleosides. Development of specific ENT4 inhibitors may open a new avenue in research on ischemic heart disease therapy.

Primary and secondary prevention of ischemic heart disease in women.

Cardiovascular disease remains the number one cause of mortality among women. With increasing awareness of heart disease in women and increasing focus on including more women in trials, mortality from cardiovascular disease has fallen. Despite this, more women than men die from cardiovascular disease, and increasing cardiovascular disease is seen in young women. Preventive therapies have been the focus of recent guidelines to close this gap. In this review, data for primary and secondary prevention therapies for ischemic heart disease in women will be reviewed.

Cardiac arrest: the changing incidence of ventricular fibrillation.

There are more than 300,000 out-of-hospital cardiac arrests (OHCA) in the USA annually, which can be grouped into those presenting with tachyarrhythmic (shockable) rhythms and those presenting with non-tachyarrhythmic rhythms. The incidence of tachyarrhythmic rhythms, which include ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT), has been noted to be progressively decreasing in multiple studies of OHCA. Improved medical and surgical therapies for ischemic heart disease, and the widespread use of implantable cardiac defibrillators (ICDs), have likely contributed to a declining incidence of VF arrest and may result in conversion of an otherwise VF event into a pulseless electrical activity (PEA) arrest. As the incidence of VF has declined, it is unclear if the absolute incidence of non-tachyarrhythmic rhythms has increased or remained largely unchanged. This article discusses the changing rates of presenting rhythms in sudden cardiac arrest, the underlying cellular mechanisms of PEA, the factors contributing to the relative increase in the rate of PEA arrests, and current treatment options.

Electromagnetic Navigation System Using Simple Coil Structure (4 Coils) for 3-D Locomotive Microrobot

Researches on the biomedical wireless microrobot are being actively carried out. In particular, compared with conventional catheter intervention, the wireless locomotive microrobot using an electromagnetic navigation system (ENS) can have many advantages in ischemic heart disease therapy. The ENSs generally use a uniform magnetic field and gradient magnetic field for the actuation of microrobots. However, because most ENSs require many coils, they have severe limitations, including a complex structure, large energy consumption, increased power supply, and large system volume. This paper proposes a new ENS for a 3-D locomotive microrobot using only four electromagnetic coils. The proposed ENS has a very simple structure, which consists of two circular coils and two saddle coils. The alignment and propulsion of the microrobot are determined by the generated magnetic field and gradient magnetic field from the four coils. This paper proposes a control algorithm and a gravity compensation for a 3-D locomotive microrobot and validates the performance of the microrobot using the proposed ENS. Finally, through a locomotion test of a blood vessel phantom, it was demonstrated that the microrobot can move to a target position in the phantom and deliver a drug to the target lesion.

Beta-blockers in the management of coronary artery disease: are we on the verge of a new paradigm shift?

Beta-adrenergic blockers remain one of the cornerstones in the management of coronary artery disease, both in chronic stable angina and myocardial infarction. These recommendations were based on studies conducted in the era prior to the establishment of the modern therapy for ischemic heart disease and myocardial infarction i.e. anti-platelet therapy, statins, and percutaneous coronary interventions. Recent studies emerged questioning the beneficial effect of beta-blockers in the management of patients with stable ischemic heart disease and myocardial infarction. In this review, we will discuss briefly the pharmacology of beta-blockers along the evidence that supports the use of beta-blockers in the management of stable ischemic heart disease and myocardial infarction. The recent studies questioning its use will also be discussed.

Similar effect of autologous and allogeneic cell therapy for ischemic heart disease: systematic review and meta-analysis of large animal studies.

In regenerative therapy for ischemic heart disease, use of both autologous and allogeneic stem cells has been investigated. Autologous cell can be applied without immunosuppression, but availability is restricted, and cells have been exposed to risk factors and aging. Allogeneic cell therapy enables preoperative production of potent cell lines and immediate availability of cell products, allowing off-the-shelf therapy. It is unknown which cell source is preferred with regard to improving cardiac function. We performed a meta-analysis of preclinical data of cell therapy for ischemic heart disease. We conducted a systematic literature search to identify publications describing controlled preclinical trials of unmodified stem cell therapy in large animal models of myocardial ischemia. Data from 82 studies involving 1415 animals showed a significant improvement in mean left ventricular ejection fraction in treated compared with control animals (8.3%, 95% confidence interval, 7.1-9.5; P<0.001). Meta-regression revealed a similar difference in left ventricular ejection fraction in autologous (8.8%, 95% confidence interval, 7.3-10.3; n=981) and allogeneic (7.3%, 95% confidence interval, 4.4-10.2, n=331; P=0.3) cell therapies. Autologous and allogeneic cell therapy for ischemic heart disease show a similar improvement in left ventricular ejection fraction in large animal models of myocardial ischemia, compared with placebo. These results are important for the design of future clinical trials.

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

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

Relationship between perioperative cardiovascular risk factors and bone marrow cells from patients undergoing coronary artery bypass grafting surgery.

Cell therapy through the implantation of autologous bone marrow cells has long been used in clinical trials for the treatment of ischemic heart diseases. However, as the outcomes of cell implantation vary among patients, risk factors that might influence the level and function of bone marrow progenitor cells should be determined, to identify patients who would benefit the most from this treatment. We collected clinical and laboratory data from 44 patients scheduled to undergo sternotomy for coronary artery bypass grafting (CABG). Bone marrow was aspirated from the sternum during the operation, and bone marrow mononuclear cells (BMMNCs) were isolated through density centrifugation. A negative correlation was observed between the number of BMMNCs and age (N = 44, r = -0.788, P = 0.001). The level of CD34+ cells in BMMNCs was 0.94 ± 0.39%, CD133+ cells 0.46 ± 0.28%, and CD34+CD133+ cells 0.53 ± 0.26%. The levels of CD34+ and CD133+ cells in diabetic patients were significantly lower than those in nondiabetic patients. Female gender, advanced age, and poor heart function were related with reduced progenitor cell clonogenic function. A positive correlation was observed between the level of CD34+ cells and BMMNC migration ability. Aging and diabetes were the major risk factors that influence the level and function of bone marrow resident progenitor cells in patients with coronary heart disease undergoing CABG. Further study is needed to determine whether these two factors can influence the outcome of bone marrow cell therapy for ischemic heart disease.

Abstract 16161: Bone Marrow Characteristics are Associated With Changes in Infarct Size Following STEMI: A Biorepository Evaluation From the CCTRN TIME Trial

OBJECTIVE: Despite significant interest in bone marrow cell mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have shown only modest benefit. However, select patients show improvements after autologous BMC therapy for unknown reasons. The purpose of this study was to identify BMC characteristics associated with infarct size reduction following STEMI. METHODS: This study evaluated prospectively the cohort of patients enrolled in the CCTRN TIME trial who agreed to their BMCs being stored and used for further analyses at the CCTRN Biorepository. Analyses were pre-specified and the core laboratories were blinded to clinical data and treatment assignments. The changes in infarct size between baseline (three days after PCI) and 6 months was measured by cMRI. BMC product underwent phenotype analysis using FACS identifying cells expressing CD45, CD34, CD31, CD133, CXCR4, CD3, CD11, CD14, and CD19 and functional analysis with the CFU-Hill, ECFC and CFU-F assays. RESULTS: Quantification of BMC characteristics and infarct size was available in 101 patients. The patients’ mean age was 56.5 years, with a mean screening ejection fraction of 37% and mean baseline cMRI ejection fraction of 45%. At 6 months, 75 (74.3%) patients had reductions in infarct size (mean -21.0% ± 17.6%). Multiple regression analysis revealed that, regardless of treatment allocation, an increased percentage of BMC that expressed CD31 (p=0.046) was associated with greater reductions in infarct size. Greater reductions in infarct size also were associated with more rapid growth rates for BMC functional assays (CFU-Hill, ECFC) (p=0.033, p=0.032, respectively). CONCLUSIONS: This study demonstrates a correlation between characteristics of BMCs in the acute STEMI phase and subsequent changes in infarct size. These data suggest that resident BMCs (specifically, endothelial precursors) play an important role in regenerating infarcted myocardium irrespective of treatment with autologous BMC transplantation.