Sodium tanshinone IIA sulfonate improves adverse ventricular remodeling post MI by reducing myocardial necrosis, modulating inflammation and promoting angiogenesis

Background and Objective: Myocardial infarction (MI) leads to pathological cardiac remodeling and heart failure. Sodium tanshinone IIA sulfonate (STS) shows therapeutic values. The present study aimed to explore the potential role of STS in ventricular remodeling post-MI Methods: Mice were randomly divided into sham, MI + normal saline (NS) and MI + STS (20.8 mg/kg/day intraperitoneally) groups. MI was established following left anterior descending artery ligation. Cardiac function was evaluated using echocardiography. Scar size and myocardial fibrosis-associated markers were detected using Masson’s trichrome staining and western blot analysis (WB). Necrosis and inflammation were assessed using H&E staining, lactate dehydrogenase (LDH) detection, ELISA, immunohistochemical staining, and WB. Furthermore, angiogenesis markers and associated proteins were detected using immunohistochemical staining and WB. Results: Mice treated with STS exhibited significant improvements in cardiac function, smaller scar size, and low expression levels of α-smooth muscle actin and collagen I and III at 28 days following surgery, compared with the NS-treated group. Moreover, treatment with STS reduced eosinophil necrosis, the infiltration of inflammatory cells, plasma levels of LDH, high mobility group protein B1, interleukin-1β and tumor necrosis factor-α, and protein expression of these cytokines at 3 days. Macrophage infiltration was also decreased in the STS group in the early phase. Additionally, CD31+ vascular density, protein levels of hypoxia-inducible factor-1α, and vascular endothelial growth factor were elevated in the STS-treated mice at 28 days. Conclusion: STS improved pathological remodeling post-MI, and the associated therapeutic effects may result from a decrease in myocardial necrosis, modulation of inflammation, and an increase in angiogenesis.

Quantitative evaluation of coronary artery occlusion by 3D coronary volume reconstruction in a large animal model of acute myocardial infarction

Background Large animal models of acute myocardial infarction (MI) offer an important platform to test novel therapies. Consistency of infarct size between animals is critical to ensure an accurate assessment of therapies against control. However, anatomical variation challenges the ability to achieve a consistent infarct size and care must be taken to respect the principles of the 3Rs through minimisation of interventional fatalities. Purpose To standardise the approach of a closed chest model of balloon occlusion-facilitated MI. Novel 3-dimensional quantitative coronary angiography (3DQCA) software has been used retrospectively to identify a correlation between coronary volume occlusion and the extension of the myocardial scar. Methods Twenty-four Yorkshire pigs (mean weight 63.1±3 kg) underwent a closed chest MI model via percutaneous occlusion of the mid portion of the left anterior descending artery (LAD) for 60 minutes. The evaluation of the myocardial damage was obtained via cardiac magnetic resonance imaging (CMR) between 24 and 48 hours after the MI model (Acute) and at 4–5 weeks after MI (Chronic). Troponin I was also measured at multiple timepoints. 3DQCA reconstruction (QAngio XA 3D, Medis medical imaging systems NL) was generated from 2 angiographic projections with segmental analysis of all 3 major epicardial vessels including lumen volume, reference diameters, and segment length. The occlusive volume and vessel length was identified through co-registration of balloon position. Results At the short term timepoint, a significant correlation was found between the LAD volume occluded and the scar size as percentage of the LV mass (Spearman correlation 0.72, p value <0.01, Fig. 1). Using Youden index analysis we identified a cut-off point of 32.8% of the LAD volume to determine a scar volume >20% (Fig. 2). At chronic phase the correlation between these two variables was not significant, although there was a trend towards significance (p value = 0.06, Cor = 0.54). No significant correlation was found with serum Troponin I. Conclusions There is a significant correlation between the LAD volume occluded and the overall scar size in the acute phase and at least 32.8% of the LAD volume should be occluded to determine a scar volume >20% of the entire LV. This indicates that a prospective measure of occluded LAD volume might minimise the intra-experimental variability in studies aiming to reduce infarct size and acute myocardial injury. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): This research work was supported by grants awarded to Professor Ascione: the British Heart Foundation (BHF) (BHF IG/14/2/30991, BHF RM/13/2/30158), and the Medical Research Council (MRC) (MRC MR/L012723/1).

Prognostic Value of Myocardial Scar In Ischemic And Non-Ischemic Cardiomyopathy Using Cardiac Magnetic Resonance Imaging

Purpose is to evaluate the prognostic value of myocardial scar/fibrosis using cardiac magnetic resonance (CMR) in patients with ischaemic cardiomyopathy (ICM) and non-ischaemic cardiomyopathy (NICM).Methods; 156 patients with either ICM or NICM underwent CMR with late gadolinium enhancement (LGE) sequences for assessment of left ventricular ejection fraction (EF), detection and quantification of any myocardial scar/fibrosis using three methods; a) manual, b) number of segments involved, c) percentage of scarred myocardium (segment based). Patients were followed up for at least 6 months for any clinical cardiac event.Results: Males were 56% (mean age 61 years), with minimal follow up (FU) of 6 months. Patients were divided into; group I; ICM (58%) and group II; NICM (36%). Clinical presentation was ranging from eventless (10%), chest pain (18%), heart failure (15%), hospitalization (35%), syncope (1%), ventricular tachycardia (<1%) and cardiac arrest (<1%). The scar mass was more in size in group I (17% ± 15) than in group II (8 % ± 13). Direct linear relationship was observed between scar size and event severity (P value < 0.001). Inverted relationship between LVEF and event severity in group I (P value of < 0.001) was detected, however, no significant correlation between LVEF and event severity in group II (P value 0.128).Conclusion: Myocardial scar size is a strong predictor for the clinical outcome in both ICM and NICM. EF is less reliable to predict morbidity in cardiomyopathy patients. Segments dependent methods for quantification of myocardial scar is comparable to the manual LGE quantifications.

MicroRNA-17-5p Downregulation Inhibits Autophagy and Myocardial Remodeling after Myocardial Infarction by Targeting STAT3

Objective: Myocardial infarction (MI) is acknowledged as a major cause of heart disease related death in the world. This study aims to explore the function and mechanism of miR-17-5p-induced STAT3 in myocardial remodeling after MI.Methods: MI mice were infected by lentivirus antago-miR-17-5p vector. The expression of miR-17-5p in myocardial tissues was detected. The levels of STAT3 and specific markers of autophagy LC3-II/LC3-I, Beclin-1 and p62 were measured. Myocardial remodeling and scar size were assessed and cell apoptosis was determined. The binding of miR-17-5p and STAT3 was analyzed. The functions of miR-17-5p and STAT3 in autophagy and myocardial remodeling after MI were confirmed by functional rescue experiment after injecting STAT3 inhibitor S31-20.Results: Decreased fractional shortening, increased left ventricular systolic diameter and ventricular filling velocity were detected in MI mice. High expression of miR-17-5p was found in myocardial tissues after MI. The inhibition of miR-17-5p expression led to reduction of fibrosis of myocardial tissues, scarring, cardiomyocyte apoptosis, and expressions of LC3-II/LC3-I and Beclin-1, and increased p62 expression after MI. miR-17-5p targeted STAT3 and negatively regulated its expression. Inhibition of STAT3 level reversed the improving effect of antago-miR-17-5p on MI.Conclusion: Inhibition of miR-17-5p can inhibit myocardial autophagy through targeting STAT3, and then inhibit myocardial remodeling, thereby protecting myocardium after MI.

Post-surgery echocardiography can predict the amount of ischemia-reperfusion injury and the resultant scar size

In spite of advances in the diagnosis and treatment of ischemic heart disease (IHD), it remains the leading cause of death globally. Thus, there is an urgent demand to investigate the underlying pathophysiology and develop new therapies for the prevention and treatment of IHD. Murine models are widely used in IHD research because they are readily available, relatively inexpensive and can be genetically modified to explore mechanistic questions. Myocardial infarction in mice is induced by the blockage followed by reperfusion of the left anterior descending branch (LAD) to imitate human IHD diseases in clinics. This ischemia/reperfusion (I/R) model can be widely used to investigate the potential reparative effect of putative treatments. However, the surgical technique is demanding and can produce an inconsistent amount of damage, which can make identification of treatment effects challenging. Therefore, determining which hearts have been significantly damaged by I/R is an important consideration in studies designed to explore either the mechanisms of disrupted function or to test possible therapies. Noninvasive echocardiography (ECHO) is often used to determine structural and functional changes in the mouse heart following injury. In the present study, we determined that ECHO performed 3 days post-I/R surgery could predict the injury produced by the ischemic insult.

Improvement of late gadolinium enhancement image quality using a deep learning–based reconstruction algorithm and its influence on myocardial scar quantification

Objectives The aim of this study was to assess the effect of a deep learning (DL)–based reconstruction algorithm on late gadolinium enhancement (LGE) image quality and to evaluate its influence on scar quantification. Methods Sixty patients (46 ± 17 years, 50% male) with suspected or known cardiomyopathy underwent CMR. Short-axis LGE images were reconstructed using the conventional reconstruction and a DL network (DLRecon) with tunable noise reduction (NR) levels from 0 to 100%. Image quality of standard LGE images and DLRecon images with 75% NR was scored using a 5-point scale (poor to excellent). In 30 patients with LGE, scar size was quantified using thresholding techniques with different standard deviations (SD) above remote myocardium, and using full width at half maximum (FWHM) technique in images with varying NR levels. Results DLRecon images were of higher quality than standard LGE images (subjective quality score 3.3 ± 0.5 vs. 3.6 ± 0.7, p < 0.001). Scar size increased with increasing NR levels using the SD methods. With 100% NR level, scar size increased 36%, 87%, and 138% using 2SD, 4SD, and 6SD quantification method, respectively, compared to standard LGE images (all p values < 0.001). However, with the FWHM method, no differences in scar size were found (p = 0.06). Conclusions LGE image quality improved significantly using a DL-based reconstruction algorithm. However, this algorithm has an important impact on scar quantification depending on which quantification technique is used. The FWHM method is preferred because of its independency of NR. Clinicians should be aware of this impact on scar quantification, as DL-based reconstruction algorithms are being used. Key Points • The image quality based on (subjective) visual assessment and image sharpness of late gadolinium enhancement images improved significantly using a deep learning–based reconstruction algorithm that aims to reconstruct high signal-to-noise images using a denoising technique. • Special care should be taken when scar size is quantified using thresholding techniques with different standard deviations above remote myocardium because of the large impact of these advanced image enhancement algorithms. • The full width at half maximum method is recommended to quantify scar size when deep learning algorithms based on noise reduction are used, as this method is the least sensitive to the level of noise and showed the best agreement with visual late gadolinium enhancement assessment.

Abstract 14080: A Phase II Randomized, Double-blind, Controlled Trial of Combined Mesenchymal Stromal Cells and C-kit+ Cardiac Progenitor Cells in Ischemic Heart Failure: The CCTRN CONCERT-HF Trial

Introduction: Although preclinical studies of cell delivery in models of ischemic heart failure (HF) suggest a beneficial interaction between mesenchymal stromal cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) resulting in additive therapeutic effects, no clinical trial has examined a combination of different cell types in ischemic HF. Furthermore, comparative studies of different cell products in humans are rare. CONCERT-HF (NCT02501811) is an NHLBI-sponsored, randomized, double-blind, placebo-controlled, Phase II trial of the Cardiovascular Cell Therapy Research Network (CCTRN) investigating feasibility, safety, and efficacy of MSCs and CPCs, alone and in combination, in patients with chronic ischemic HF. Objectives: To address the following questions: Is combined treatment with MSCs and CPCs feasible and safe in patients with ischemic HF? Do MSCs and CPCs, given alone or in combination, alleviate LV dysfunction, reduce scar size, improve quality of life, and/or augment functional capacity? Is either cell type more effective than the other? Is the combination of MSCs and CPCs more efficacious than MSCs alone or CPCs alone? Methods: Patients were randomized (1:1:1:1) to receive i) the combination of autologous bone marrow-derived MSCs and autologous CPCs, ii) MSCs alone, iii) CPCs alone, or iv) placebo. Target doses were 150 x 10 6 MSCs and 5 x 10 6 CPCs. All patients underwent bone marrow aspiration and right heart catheterization. Endomyocardial biopsy was performed only in the MSC + CPC and CPC alone groups; a “sham biopsy” was performed in the MSC alone and placebo groups. All patients underwent study product injection using the NOGA ® XP Mapping System and were followed for 12 months. Results: A total of 125 patients (116 M, 9 F), 62.5 ± 8.9 years old, were enrolled at 7 CCTRN centers between Nov 2016 and Oct 2018. Baseline LVEF (cardiac MRI) was 28.6 ± 6.1% with a mean scar size of 31.8 ± 10.9 g and NYHA class II (80%) or class III (15.2%). Conclusions: CONCERT-HF is the first cell therapy trial to assess a combination of different cell types and to directly compare two different cell products in patients with HF. All patients will complete follow-up by the end of June and final primary (12-month) safety and outcomes data will be available in August 2020.

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.

Abstract 12730: Cardiosphere-derived Cells Improve Segmental Myocardial Circumferential Strain by Magnetic Resonance Imaging: Results From the Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration Study

Introduction: Cell therapy failed to improve global LV ejection fraction (LVEF) in most trials of post-MI LV dysfunction. LVEF does not consider the effect of cell therapy on different segments of the myocardium, which may be heterogeneous across different myocardial regions in patients with regional MI. Hypothesis: Allogeneic cardiosphere-derived cells (CDCs) improve segmental (but not global) myocardial function indexed as circumferential strain by MRI. Methods: In this randomized double-blind trial, 142 post-MI patients with LVEF<45% and 15% or greater LV scar size were randomized in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6-month was compared between CDCs and placebo groups. Results: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3(10.8) and 108 (87.1%) males). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5%(4.0)) compared to placebo (0.2%(3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs. 0.04% (3.7) in the placebo group, p=0.04). The beneficial effect of CDCs for improving segmental Ecc was greater in patients with LV ejection fraction<41%, LV scar size>18.8% or LV end-diastolic volume index>100 [mixed effect regression coefficients of -0.92(p=0.02),-0.78(p=0.03), and -1.16(p=0.004) respectively versus -0.58(p=0.05) for the entire cohort]. Conclusions: In patients with post-MI LV dysfunction, allogeneic CDC administration resulted in improved segmental myocardial function. This CDC induced improvement in segmental myocardial function was greater in patients with severe LV dysfunction, dilated LV and greater infarct size. (clinicaltrials.gov Identifier: NCT01458405).