Therapy For Ischemic Heart Disease Research Articles

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.

Abstract 12836: Low-Intensity Pulsed Ultrasound Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia -Potential Involvement of Mechanotransduction

Purpose: Despite recent progress in the management of ischemic heart disease (IHD), the number of patients with severe IHD is increasing. In this study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD and to elucidate the underlying molecular mechanisms for the LIPUS-induced angiogenesis. Methods and Results: We first confirmed that the LIPUS up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle in cultured human vascular endothelial cells (HUVECs). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n=28). The heart was treated with either sham or LIPUS (32-cycle, 20 min) at 3 different short axis levels (n=14 each). Four weeks after the therapy, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P&lt;0.05), whereas it remained unchanged in the control group. Capillary density and regional myocardial blood flow in the ischemic region were also increased in the LIPUS group but not in the control group. The protein expressions of VEGF, eNOS and bFGF in the ischemic area were enhanced in the LIPUS group compared with the control group. To further examine the signaling pathways responsible for the LIPUS-induced angiogenesis, HUVECs were transfected with siRNA or scrambled siRNA of either β1 integrin or caveolin-1. Knockdown of either β1 integrin or caveolin-1 with siRNA suppressed the LIPUS-induced up-regulation of VEGF. siRNA-mediated suppression of either focal adhesion kinase (FAK) or Fyn also inhibited the LIPUS-induced up-regulation of VEGF. Knockdown of these molecules with siRNA was confirmed with real-time PCR. Conclusions: These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD and that β1 integrin and caveolin-1 may be involved in underlying molecular mechanisms for the beneficial effects of the LIPUS.

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

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

Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer.

Despite the promise shown by stem cells for restoration of cardiac function after myocardial infarction, the poor survival of transplanted cells has been a major issue. Hypoxia-inducible factor-1 (HIF1) is a transcription factor that mediates adaptive responses to ischemia. Here, we hypothesize that codelivery of cardiac progenitor cells (CPCs) with a nonviral minicircle plasmid carrying HIF1 (MC-HIF1) into the ischemic myocardium can improve the survival of transplanted CPCs. After myocardial infarction, CPCs were codelivered intramyocardially into adult NOD/SCID mice with saline, MC-green fluorescent protein, or MC-HIF1 versus MC-HIF1 alone (n=10 per group). Bioluminescence imaging demonstrated better survival when CPCs were codelivered with MC-HIF1. Importantly, echocardiography showed mice injected with CPCs+MC-HIF1 had the highest ejection fraction 6 weeks after myocardial infarction (57.1±2.6%; P=0.002) followed by MC-HIF1 alone (48.5±2.6%; P=0.04), with no significant protection for CPCs+MC-green fluorescent protein (44.8±3.3%; P=NS) when compared with saline control (38.7±3.2%). In vitro mechanistic studies confirmed that cardiac endothelial cells produced exosomes that were actively internalized by recipient CPCs. Exosomes purified from endothelial cells overexpressing HIF1 had higher contents of miR-126 and miR-210. These microRNAs activated prosurvival kinases and induced a glycolytic switch in recipient CPCs, giving them increased tolerance when subjected to in vitro hypoxic stress. Inhibiting both of these miRs blocked the protective effects of the exosomes. In summary, HIF1 can be used to modulate the host microenvironment for improving survival of transplanted cells. The exosomal transfer of miRs from host cells to transplanted cells represents a unique mechanism that can be potentially targeted for improving survival of transplanted cells.

Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia.

BackgroundAlthough a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD.Methods and ResultsWe first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm2 for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm2, P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group.ConclusionsThese results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.

SIMILAR EFFECT OF AUTOLOGOUS AND ALLOGENEIC CELL THERAPY FOR ISCHEMIC HEART DISEASE: RESULTS FROM A META-ANALYSIS OF LARGE ANIMAL STUDIES

In regenerative therapy for ischemic heart disease, use of both autologous and allogeneic stem cells have been investigated. Autologous cells can be applied without immunosuppression but availability is restricted and cells have been exposed to risk factors and aging. Allogeneic cell therapy enables

S-Propargyl-Cysteine, a Novel Water-Soluble Modulator of Endogenous Hydrogen Sulfide, Promotes Angiogenesis Through Activation of Signal Transducer and Activator of Transcription 3

Conventional revascularization strategies or drug therapies for ischemic heart disease (IHD) are designed for reperfusion of coronary arteries to salvage cardiomyocytes, but occasionally, myocardial reperfusion injury can occur because of microcirculatory dysfunction. Therefore, a more microcirculation-friendly strategy should be explored to overcome and compensate for the shortcomings of conventional strategies. In this work, we investigated the proangiogenic effect of S-Propargyl-Cysteine (SPRC), a novel water-soluble modulator of endogenous hydrogen sulfide, and elucidated the possible mechanisms involved to provide an experimental basis for angiogenesis-mediated drug therapy for IHD. SPRC promoted cell proliferation, adhesion, migration, and tube formation of primary human umbilical vein endothelial cells (HUVEC) and increased angiogenesis in the rat aortic ring and Matrigel plug models. In a mouse model of hindlimb ischemia and a rat model of myocardial ischemia, SPRC also promoted angiogenesis after ligation of the left femoral artery or coronary artery to ameliorate ischemic conditions. In primary HUVEC, STAT3 phosphorylation was significantly induced after SPRC treatment. The critical roles of STAT3 in mediating the proangiogenic effect of SPRC were confirmed by RNA interference. Co-crystallization excluded the possible direct interaction between SPRC and STAT3, whereas co-immunoprecipitation revealed an enhanced interaction between VEGFR2 and STAT3 after SPRC treatment. Meanwhile, immunofluorescence and chromatin immunoprecipitation showed that SPRC induced the nuclear translocation of STAT3, followed by transcriptional activation of downstream promoters, particularly the Vegf promoter. We present a novel STAT3-mediated mechanism in SPRC-induced angiogenesis and demonstrate the therapeutic potential of SPRC in ischemic disease through angiogenesis promotion.

Lessons Learned from Negative Clinical Trials Evaluating Antithrombotic Therapy for Ischemic Heart Disease

The clinical trials that failed to demonstrate significant efficacy may not result in development of new therapy but contribute to better understanding of antithrombotic therapy for ischemic heart disease. Negative trials provide important messages about how to interpret and understand the results of clinical trials and apply these results to clinical practices. Although every aspect of clinical trials may influence the outcomes of trials and interpretation of their results, selection of study subjects, endpoints, and measuring risk/benefit are crucial to success of clinical trial. We will review the recent key negative trials on antithrombotic therapy for ischemic heart disease and discuss about their results and implications. The challenge in the future for the development of antithrombotic therapies is to leverage these "lessons learned" from negative clinical trials to improve the design, conduct, and interpretation of future randomized clinical trials.

Comparison Between Ivabradine and Low-Dose Digoxin in the Therapy of Diastolic Heart Failure with Preserved Left Ventricular Systolic Function

Multicenter trials have demonstrated that in patients with sinus rhythm ivabradine is effective in the therapy of ischemic heart disease and of impaired left ventricular systolic function. Ivabradine is ineffective in atrial fibrillation. Many patients with symptomatic heart failure have diastolic dysfunction with preserved left ventricular systolic function, and many have asymptomatic paroxysmal atrial fibrillation. Ivabradine is not indicated in these conditions, but it happens that it is erroneously used. Digoxin is now considered an outdated and potentially dangerous drug and while effective in the mentioned conditions, is rarely used. The aim of the study was to compare the therapeutic effects of ivabradine in diastolic heart failure with preserved left ventricular systolic function. Patients were assigned to ivabradine or digoxin according to a randomization cross-over design. Data were single-blind analyzed. The analysis was performed using an intention-to-treat method. Forty-two coronary patients were selected. In spite of maximally tolerated therapy with renin-antagonists, diuretics and β-blockers, they had congestive diastolic heart failure with preserved systolic function. Both ivabradine and digoxin had positive effects on dyspnea, Nterminal natriuretic peptide, heart rate, duration of 6-min. walk-test and signs of diastolic dysfunction, but digoxin was high-statistically more effective. Side-effects were irrelevant. Data were obtained in a single-center and from 42 patients with ischemic etiology of heart failure. The number of patients is small and does not allow assessing mortality. In coronary patients with symptomatic diastolic heart failure with preserved systolic function low-dose digoxin was significantly more effective than ivabradine and is much cheaper. One should be more critical about ivabradine and low-dose digoxin in diastolic heart failure. To avoid possible negative effects on the cardiac function and a severe reduction of the cardiac output the resting heart rate should not be decreased to <65 beats/min.

Effects of ischemic preconditioning on myocardium Caspase-3, SOCS-1, SOCS-3, TNF-α and IL-6 mRNA expression levels in myocardium IR rats

The aim of this study was to characterise the effects of ischemic preconditioning (IP) on heart function parameters (ΔST and ΔT), activities of serum creatine kinase (CK), lactate dehydrogenase (LDH), and levels of serum nitric oxide (NO), malondialdehyde (MDA), and myocardium Caspase-3 mRNA, SOCS-1, SOCS-3, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) expression levels and Apoptosis index in myocardium IR rats. Results showed that ΔST and ΔST values in IP group were markedly lower than those in IR group. Compared with IR group, IP significantly (p < 0.01) decreased serum CK (0.83 ± 0.09 vs 1.36 ± 0.15), LDH (5613 ± 462 vs 7106 ± 492) activities and MDA (11.32 ± 1.05 vs 15.49 ± 1.26) level, increased the serum NO (86.39 ± 7.03 vs 53.77 ± 4.27) level in IR group. The IP induced a significant decreased in myocardium Caspase-3 mRNA (0.303 ± 0.021 vs 0.515 ± 0.022) gene expression (p < 0.01) compared to IR model group. The IP induced a significant decreased in myocardium SOCS-1 (0.241 ± 0.031 vs 0.596 ± 0.036), SOCS-3 (0.258 ± 0.031 vs 0.713 ± 0.057), TNF-α (0.137 ± 0.011 vs 0.427 ± 0.035) and IL-6 (0.314 ± 0.021 vs 0.719 ± 0.064) mRNA gene expression (p < 0.01) compared to IR model group. We conclude that IP is effective in the therapy of heart disease. These findings may have implications for the clinical development of preconditioning-based therapies for ischemic heart disease.

Normalization of Postinfarct Biomechanics Using a Novel Tissue-Engineered Angiogenic Construct

Cell-mediated angiogenic therapy for ischemic heart disease has had disappointing results. The lack of clinical translatability may be secondary to cell death and systemic dispersion with cell injection. We propose a novel tissue-engineered therapy, whereby extracellular matrix scaffold seeded with endothelial progenitor cells (EPCs) can overcome these limitations using an environment in which the cells can thrive, enabling an insult-free myocardial cell delivery to normalize myocardial biomechanics. EPCs were isolated from the long bones of Wistar rat bone marrow. The cells were cultured for 7 days in media or seeded at a density of 5 × 10(6) cells/cm(2) on a collagen/vitronectin matrix. Seeded EPCs underwent ex vivo modification with stromal cell-derived factor-1α (100 ng/mL) to potentiate angiogenic properties and enhance paracrine qualities before construct formation. Scanning electron microscopy and confocal imaging confirmed EPC-matrix adhesion. In vitro vasculogenic potential was assessed by quantifying EPC cell migration and vascular differentiation. There was a marked increase in vasculogenesis in vitro as measured by angiogenesis assay (8 versus 0 vessels/hpf; P=0.004). The construct was then implanted onto ischemic myocardium in a rat model of acute myocardial infarction. Confocal microscopy demonstrated a significant migration of EPCs from the construct to the myocardium, suggesting a direct angiogenic effect. Myocardial biomechanical properties were uniaxially quantified by elastic modulus at 5% to 20% strain. Myocardial elasticity normalized after implant of our tissue-engineered construct (239 kPa versus normal=193, P=0.1; versus infarct=304 kPa, P=0.01). We demonstrate restoration and normalization of post-myocardial infarction ventricular biomechanics after therapy with an angiogenic tissue-engineered EPC construct.