A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model

The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy’s potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure–volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure–volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

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Abstract 16165: Embryonic Stem Cell-derived Cardiomyocytes Increase Viable Myocardium but Do Not Improve Function in a Mouse Model of Chagasic Cardiomyopathy

Circulation ◽

10.1161/circ.132.suppl_3.16165 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Adriana B Carvalho ◽

Guilherme V Brasil ◽

Danubia Silva-dos-Santos ◽

Fernanda P Mesquita ◽

Tais H Kasai-Brunswick ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Function ◽

Embryonic Stem ◽

The United States ◽

Left Ventricular ◽

Viable Myocardium ◽

Left Ventricular Ejection ◽

Intramyocardial Injection ◽

Ventricular Ejection Fraction ◽

Chagasic Cardiomyopathy

Chagas disease is a parasitic infection caused by Trypanosoma cruzi ( T. cruzi ). It is endemic in Latin America but cases have been increasing in the United States due to the migration of infected individuals. The objective of this work was to evaluate the effects of cell therapy with cardiomyocytes derived from mouse embryonic stem cells (CM-mESC) in a mouse model of chronic chagasic cardiomyopathy. CD1 mice were infected with the Brazil strain of T. cruzi . After 5 months, cardiac function was evaluated by magnetic resonance imaging (MRI) (Table 1). Left ventricular ejection fraction (LVEF) was decreased in infected animals when compared to non-infected controls, while LV end-diastolic volume (EDV) and LV end-systolic volume were increased. Right ventricular (RV) EF was not altered. However, RVEDV and RVESV were increased in the infected group when compared to non-infected animals. mESC E14TG2A line was differentiated into cardiomyocytes and efficiency was confirmed by troponin T staining. 8x10^5 CM-mESC were delivered by echocardiography-guided intramyocardial injection only if cardiomyocyte differentiation efficiency was above 70%. Cell tracking was performed by bioluminescence and MRI using luciferase-transduced cells and iron oxide nanoparticles, respectively. CM-mESC were detected in the heart for at least 8 days. After 45 days, MRI data showed no changes in LV or RV EF and volumes (Table 1). Sirius red staining was performed and the areas of viable myocardium and fibrosis were quantified by morphometry. Although no functional improvement was detected by MRI, there was a significant increase in viable myocardium when CM-mESC-treated mice were compared to placebo-treated animals. In conclusion, a single injection of CM-mESC in a mouse model of chagasic cardiomyopathy contributes to myocardial repair. However, this was insufficient to promote an improvement of cardiac function, which may require multiple cardiomyocyte injections.

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Injection of autologous bone marrow cells in hyaluronan hydrogel improves cardiac performance after infarction in pigs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00801.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. H1078-H1086 ◽

Cited By ~ 24

Author(s):

Chien-Hsi Chen ◽

Ming-Yao Chang ◽

Shoei-Shen Wang ◽

Patrick C. H. Hsieh

Keyword(s):

Bone Marrow ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Normal Saline ◽

Left Ventricular ◽

Ventricular Ejection ◽

Left Ventricular Ejection ◽

Coronary Artery Ligation ◽

Intramyocardial Injection ◽

Ventricular Ejection Fraction

Intramyocardial injection of bone marrow mononuclear cells (MNCs) with hyaluronan (HA) hydrogel is beneficial to the ischemic heart in a rat model of myocardial infarction (MI). However, the therapeutic efficacy and safety must be addressed in large animals before moving onto a clinical trial. Therefore, the effect of combined treatment on MI was investigated in pigs. Coronary artery ligation was performed in minipigs to induce MI followed by an intramyocardial injection of normal saline ( n = 7), HA ( n = 7), normal saline with 1 × 108 freshly isolated MNCs ( n = 8), or HA with 1 × 108 MNCs (HA-MNC; n = 7), with a sham-operated group serving as a control ( n = 7). The response of each experimental group was estimated by echocardiography, ventricular catheterization, and histological analysis. Although injection of HA or MNCs slightly elevated left ventricular ejection fraction, the combined HA-MNC injection showed a significant increase in left ventricular ejection fraction, contractility, infarct size, and neovascularization. Importantly, injection of MNCs with HA also promoted MNC retention and MNC differentiation into vascular lineage cells in pigs. Therefore, this study not only provides evidence but also raises the possibility of using a combined HA-MNC injection as a promising therapy for heart repair.

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EARLY OUTCOME AFTER AORTIC VALVE REPLACEMENT ON PATIENTS WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2014.1.5 ◽

2014 ◽

pp. 31-36

Author(s):

Quang Thuu Le

Keyword(s):

Septal Defect ◽

Intraoperative Complications ◽

Systolic Pressure ◽

Atrioventricular Septal Defect ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Mitral Insufficiency ◽

Atrioventricular Valve ◽

Ventricular Ejection Fraction ◽

Mitral Incompetence

Background: To evaluate the early results of operation for partial atrioventricular septal defect. Methods: Twenty-sevent patients underwent surgical correction of partial atrioventricular septal defect from 1/2011 to 12/2013 at Cardiovascular Centre of Hue Central Hospital. There were 7 (25.9%) female patients and 20 (74.1%) male patients, 18.5% of patients aged < 1 age, 55.6% of patients aged ≥ 1 to 15 years, and 25.9% of patients aged ≥ 16 to 60 years. Sevent (25.9%) had congestive heart failure. There was a primum atrial septal defect in 100% of patients. A cleft of the anterior mitral leaflet was diagnosed in 100% of patients. 92.6% of patients had either moderate or severe mitral incompetence prior to operation. The pulmonary artery systolic pressure exceeded 40 mmHg in 85,.2% of patients. Results: Atrial septal defects were closed with a pericardial patch in 100% of patients. The cleft in its anterior leaflet was closed in 100% of patients. Postoperatively, moderate mitral insufficiency developed in 14.8% of patients. 85.2% of patients have mild mitral incompetence. One patients (3.7%) needed a permanent pacemaker. There was no intraoperative mortality. At 6-9 months postoperatively, left atrioventricular valve insufficiency was moderate in 2 (7.4%) patients and mild in 25 (92.6%) patients who had had cleft closure alone. Conclusions: Repair of partial atrioventricular septal defect is safe and good. It is important to close the cleft in the left atrioventricular valve. The mitral valve should be repaired in a conservative manner. Intraoperative complications occur but are uncommon, suggesting that short-term follow is excellent.

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The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

Cell & Bioscience ◽

10.1186/s13578-020-00523-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jingtao Na ◽

Haifeng Jin ◽

Xin Wang ◽

Kan Huang ◽

Shuang Sun ◽

...

Keyword(s):

Heart Failure ◽

Expression Patterns ◽

Systolic Pressure ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Ventricular Pressure ◽

Luciferase Reporter ◽

Left Ventricular Ejection ◽

Tunel Staining ◽

Ventricular Ejection Fraction

Abstract Background Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3. Methods Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry. Results HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and −dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined. Conclusion Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.

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A Randomized Controlled Trial to Study the Effect of Yoga Therapy on Cardiac Function and N Terminal Pro BNP in Heart Failure

Integrative Medicine Insights ◽

10.4137/imi.s13939 ◽

2014 ◽

Vol 9 ◽

pp. IMI.S13939 ◽

Cited By ~ 12

Author(s):

Bandi Hari Krishna ◽

Pravati Pal ◽

G. K. Pal ◽

J. Balachander ◽

E. Jayasettiaseelon ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Medical Therapy ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Control Group ◽

Tei Index ◽

Ventricular Ejection Fraction ◽

Yoga Therapy ◽

Standard Medical Therapy

Aims The purpose of this study was to evaluate whether yoga training in addition to standard medical therapy can improve cardiac function and reduce N terminal pro B-type natriuretic peptide (NT pro BNP) in heart failure (HF). Methods 130 patients were recruited and randomized into two groups: Control Group (CG) ( n = 65), Yoga Group (YG). In YG, 44 patients and in CG, 48 patients completed the study. Cardiac function using left ventricular ejection fraction (LVEF), myocardial performance index (Tei index), and NT pro BNP, a biomarker of HF, was assessed at baseline and after 12 weeks. Result Improvement in LVEF, Tei index, and NT pro BNP were statistically significant in both the groups. Furthermore, when the changes in before and after 12 weeks were in percentage, LVEF increased 36.88% in the YG and 16.9% in the CG, Tei index was reduced 27.87% in the YG and 2.79% in the CG, NT pro BNP was reduced 63.75% in the YG and 10.77% in the CG. The between group comparisons from pre to post 12 weeks were significant for YG improvements (LVEF, P < 0.01, Tei index, P < 0.01, NT pro BNP, P < 0.01). Conclusion These results indicate that the addition of yoga therapy to standard medical therapy for HF patients has a markedly better effect on cardiac function and reduced myocardial stress measured using NT pro BNP in patients with stable HF.

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Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽

10.1161/circ.116.suppl_16.ii_246-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Satoshi Okumura ◽

Yunzhe Bai ◽

Meihua Jin ◽

Sayaka Suzuki ◽

Akiko Kuwae ◽

...

Keyword(s):

Heart Failure ◽

Cyclic Amp ◽

Transgenic Mice ◽

Cardiac Function ◽

Proinflammatory Cytokines ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

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Abstract 177: Ticagrelor, but not Clopidogrel, Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.177 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Yumei Ye ◽

Jose R Perez-Polo ◽

Manjyot K Nanhwan ◽

Sven Nylander ◽

Yochai Birnbaum

Keyword(s):

Myocardial Infarction ◽

Platelet Aggregation ◽

Reperfusion Injury ◽

Heart Function ◽

Oral Treatment ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Control Group ◽

Coronary Artery Ligation ◽

Ventricular Ejection Fraction

Background: Clopidogrel (C) and Ticagrelor (T) are P2Y12 ADP receptor antagonists. In addition, ticagrelor inhibits adenosine cell uptake. In PLATO trial T reduced the incidence of the primary composite endpoint myocardial infarction, stroke or cardiovascular death over C in patients with acute coronary syndromes. Previous data show that 7d pretreatment with T limits infarct size (IS) in rats. We compared the effects of C and T, administered just before reperfusion on IS. We also assessed the effect of T and C, administered just before reperfusion and/or 6w oral treatment on cardiac remodeling. Methods: Rats underwent 30min coronary artery ligation. 1) At 25min of ischemia rats received intraperitoneal (IP) vehicle, T (10 or 30mg/kg), or C (12.5mg/kg). Area at risk (AR) was assessed by blue dye and IS by TTC staining 24h after reperfusion. 2) Rats received vehicle without (sham) or with (control) coronary ischemia, T (30mg/kg) IP (TIP), T (300mg/kg/d) oral for 6w, started a day after reperfusion (TPO), TIP+PO (TIPPO), or C (12.5mg/kg IP +62.5mg/kg/d PO for 6w). LV dimensions and function was assessed by echo at 6w. Results: 1) AR was comparable among groups. IS was 45.3±1.7% of the AR in the control group. T10 (31.5±1.8%; p=0.001) and T30 (21.4±2.6% p<0.001) significantly reduced IS, whereas C (42.4±2.6%) had no effect. Platelet aggregation in the controls was 64.7±1.3% and was comparable in T30 (24.9±1.8%) and C (23.2±1.8%) at 2h post reperfusion. T30 increased Akt, eNOS and ER1/2 phosphorylation 4h after reperfusion, whereas C had no effect. 2) Platelet aggregation at 1w oral treatment was 59.7±3.2% in the control group and was comparable in TIPPO (18.1±1.3%) and C (17.4±0.7%). Left ventricular ejection fraction was 77.6±0.9%*, 44.8±3.5%, 69.5±1.6%*, 69.2±1.0%*, 76.3±1.2%*, and 37.4±3.7% in the sham, vehicle, TIP, TPO, TIPPO and C treated group, respectively (*p<0.001 vs. vehicle). Left ventricular diameters at diastole and systole showed the same pattern. Conclusions: T, but not C, administered just before reperfusion protects against reperfusion injury. Oral T (in combination or not with acute treatment just before reperfusion) treatment for 6w improves heart function. C, despite achieving similar degree of platelet inhibition had no effect on remodeling.

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Effects of Exercise on Cardiac Function Outcomes in Women Receiving Anthracycline or Trastuzumab Treatment for Breast Cancer: A Systematic Review and Meta-Analysis

Applied Sciences ◽

10.3390/app11188336 ◽

2021 ◽

Vol 11 (18) ◽

pp. 8336

Author(s):

Pedro Antunes ◽

Dulce Esteves ◽

Célia Nunes ◽

Anabela Amarelo ◽

José Fonseca-Moutinho ◽

...

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Cardiac Function ◽

Meta Analysis ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Cochrane Library ◽

Circulating Biomarkers ◽

Ventricular Ejection Fraction ◽

Secondary Outcomes

Background: we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of exercise training on cardiac function and circulating biomarkers outcomes among women with breast cancer (BC) receiving anthracycline or trastuzumab-containing therapy. Methods: PubMed, EMBASE, Cochrane Library, Web of Science and Scopus were searched. The primary outcome was change on left ventricular ejection fraction (LVEF). Secondary outcomes included diastolic function, strain imaging and circulating biomarkers. Results: Four RCTs were included, of those three were conducted during anthracycline and one during trastuzumab, involving 161 patients. All trials provided absolute change in LVEF (%) after a short to medium-term of treatment exposure (≤6 months). Pooled data revealed no differences in LVEF in the exercise group versus control [mean difference (MD): 2.07%; 95% CI: −0.17 to 4.34]. Similar results were observed by pooling data from the three RCTs conducted during anthracycline. Data from trials that implemented interventions with ≥36 exercise sessions (n = 3) showed a significant effect in preventing LVEF decline favoring the exercise (MD: 3.25%; 95% CI: 1.20 to 5.31). No significant changes were observed on secondary outcomes. Conclusions: exercise appears to have a beneficial effect in mitigating LVEF decline and this effect was significant for interventions with ≥36 exercise sessions.

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Is Skeletal Myoblast Transplantation Clinically Relevant in the Era of Angiotensin-Converting Enzyme Inhibitors?

Circulation ◽

10.1161/circ.104.suppl_1.i-223 ◽

2001 ◽

Vol 104 (suppl_1) ◽

Author(s):

Bruno Pouzet ◽

Saïd Ghostine ◽

Jean-Thomas Vilquin ◽

Isabelle Garcin ◽

Marcio Scorsin ◽

...

Keyword(s):

Ejection Fraction ◽

Cell Transplantation ◽

Ace Inhibitors ◽

Culture Medium ◽

Ace Inhibitor ◽

Ex Vivo ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Coronary Artery Ligation ◽

Ventricular Ejection Fraction

Background There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors. Methods and Results A myocardial infarction was created in 99 rats by coronary artery ligation. They were divided into 4 groups. Two groups did not receive any drug and were intramyocardially injected 7 days after the infarct with either culture medium alone (control rats, n=16) or autologous SM cells (2.3×10 6 myoblasts) previously expanded ex vivo for 7 days (myoblasts, n=24). Two other groups received the ACE inhibitor perindoprilat (1 mg · kg −1 · d −1 ), started the day of the infarct and continued uninterruptedly thereafter, and underwent time-matched procedures, that is, they were intramyocardially injected at 7 days after infarction with either culture medium alone (ACE inhibitors, n=22) or autologous SM cells (2.5×10 6 myoblasts) previously expanded ex vivo for 7 days (ACE inhibitors+myoblasts, n=37). Left ventricular function was assessed by 2D echocardiography. At the end of the 2-month study, left ventricular ejection fraction (%, mean±SEM) was increased in all groups (myoblasts, 37.4±1.2; ACE inhibitors, 31.6±1.7; ACE inhibitors+myoblasts, 43.9±1.4) compared with that in control rats (19.8±0.7) ( P <0.0001). The improvement in ejection fraction was similar in the ACE inhibitor and the myoblast groups (31.6±1.7 versus 37.4±1.2, P =0.0636). However, in the ACE inhibitor+myoblast group, this improvement was greater than that seen in hearts receiving either treatment alone (43.9±1.4 versus 31.6±1.7 in the ACE inhibitor group and 43.9±1.4. versus 37.4±1.2 in the myoblast group, P <0.0001 and P =0.0084, respectively). Conclusions These data provide further support for the clinical relevance of autologous SM cell transplantation in that its cardioprotective effects are additive to those observed with ACE inhibitors.

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Intramyocardial Transplantation of Autologous Myoblasts

Circulation ◽

10.1161/circ.102.suppl_3.iii-210 ◽

2000 ◽

Vol 102 (suppl_3) ◽

Author(s):

Bruno Pouzet ◽

Jean-Thomas Vilquin ◽

Albert A. Hagège ◽

Marcio Scorsin ◽

Emmanuel Messas ◽

...

Keyword(s):

Left Ventricular ◽

Left Ventricular Ejection ◽

Coronary Artery Ligation ◽

Skeletal Myoblast ◽

Artery Ligation ◽

Ventricular Ejection Fraction ◽

Muscle Conditioning ◽

2D Echocardiography ◽

Complex Process ◽

Autologous Myoblasts

Background —Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique. Methods and Results —Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300, P =0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5×10 6 , n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean±SEM) was increased only in the cultured SM–transplanted group at 1 ( P =0.0006) and 2 months ( P =0.0008) versus baseline (37.52±1.92 and 40.92±2.17 versus 30.34±1.74), with a significant additional benefit between 1 and 2 months ( P =0.0069). Conclusions —Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.

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