Publications by authors named "Eduardo Marbán"

244 Publications

Basic and Translational Research in Cardiac Repair and Regeneration: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Nov;78(21):2092-2105

Mandel Center for Hypertension Research, Duke Cardiovascular Center, Duke University School of Medicine, Durham, North Carolina, USA.

This paper aims to provide an important update on the recent preclinical and clinical trials using cell therapy strategies and engineered heart tissues for the treatment of postinfarction left ventricular remodeling and heart failure. In addition to the authors' own works and opinions on the roadblocks of the field, they discuss novel approaches for cardiac remuscularization via the activation of proliferative mechanisms in resident cardiomyocytes or direct reprogramming of somatic cells into cardiomyocytes. This paper's main mindset is to present current and future strategies in light of their implications for the design of future patient trials with the ultimate objective of facilitating the translation of discoveries in regenerative myocardial therapies to the clinic.
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http://dx.doi.org/10.1016/j.jacc.2021.09.019DOI Listing
November 2021

Extracellular Vesicles Secreted by TDO2-Augmented Fibroblasts Regulate Pro-inflammatory Response in Macrophages.

Front Cell Dev Biol 2021 22;9:733354. Epub 2021 Oct 22.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Extracellular vesicles (EVs) are secreted lipid bilayer vesicles that mediate cell to cell communication and are effectors of cell therapy. Previous work has shown that canonical Wnt signaling is necessary for cell and EV therapeutic potency. Tryptophan 2,3-dioxygenase (TDO2) is a target gene of canonical Wnt signaling. Augmenting TDO2 in therapeutically inert fibroblasts endows their EVs with immunomodulatory capacity including attenuating inflammatory signaling in macrophages. Transcriptomic analysis showed that macrophages treated with EVs from fibroblasts overexpressing TDO2 had blunted inflammatory response compared to control fibroblast EVs. , EVs from TDO2-overexpressing fibroblasts preserved cardiac function. Taken together, these results describe the role of a major canonical Wnt-target gene (TDO2) in driving the therapeutic potency of cells and their EVs.
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http://dx.doi.org/10.3389/fcell.2021.733354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571098PMC
October 2021

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury.

Front Cell Dev Biol 2021 23;9:733158. Epub 2021 Sep 23.

Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States.

Pulmonary fibrosis is a progressive disease for which no curative treatment exists. We have previously engineered dermal fibroblasts to produce extracellular vesicles with tissue reparative properties dubbed activated specialized tissue effector extracellular vesicles (ASTEX). Here, we investigate the therapeutic utility of ASTEX and in a mouse model of bleomycin-induced lung injury. RNA sequencing demonstrates that ASTEX are enriched in micro-RNAs (miRs) cargo compared with EVs from untransduced dermal fibroblast EVs (DF-EVs). Treating primary macrophages with ASTEX reduced interleukin (IL)6 expression and increased IL10 expression compared with DF-EV-exposed macrophages. Furthermore, exposure of human lung fibroblasts or vascular endothelial cells to ASTEX reduced expression of smooth muscle actin, a hallmark of myofibroblast differentiation (respectively). , intratracheal administration of ASTEX in naïve healthy mice demonstrated a favorable safety profile with no changes in body weight, lung weight to body weight, fibrotic burden, or histological score 3 weeks postexposure. In an acute phase (short-term) bleomycin model of lung injury, ASTEX reduced lung weight to body weight, IL6 expression, and circulating monocytes. In a long-term setting, ASTEX improved survival and reduced fibrotic content in lung tissue. These results suggest potential immunomodulatory and antifibrotic properties of ASTEX in lung injury.
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http://dx.doi.org/10.3389/fcell.2021.733158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512699PMC
September 2021

Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure.

Circ Res 2021 Oct 13. Epub 2021 Oct 13.

Heart Institute, Cedars-Sinai Medical Center, UNITED STATES.

Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed. Dahl salt-sensitive rats fed a high-salt diet, with echocardiographically-verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt-sensitive rats receiving low salt diet served as controls. Protein, and phosphorylated Ser, Thr and Tyr residues from left ventricular tissue, were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared to control. Of those 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment. Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316311DOI Listing
October 2021

A phoenix rises from the ashes of cardiac cell therapy.

Authors:
Eduardo Marbán

Nat Rev Cardiol 2021 Nov;18(11):743-744

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1038/s41569-021-00625-1DOI Listing
November 2021

Pituitary somatotroph adenoma-derived exosomes: characterization of nonhormonal actions.

J Clin Endocrinol Metab 2021 Sep 1. Epub 2021 Sep 1.

Department of Medicine, Los Angeles, California, USA.

Context: Identification and biological actions of pituitary-derived exosomes remain elusive.

Objective: To validate production of exosomes derived from human and rat pituitary and elucidate their actions.

Methods: Isolated extracellular vesicles (EVs) were analyzed by Nanoparticle Tracking Analysis (NTA) and expressed exosomal markers detected by Western blot, using non-pituitary fibroblast FR and myoblast H9C2 cells as controls. Exosome inhibitor GW4869 was employed to detect attenuated EV release. Exosomal RNA contents were characterized by RNA-seq. In vitro and in vivo hepatocyte signaling alterations responding to GH1-derived exosomes (GH1-exo) were delineated by mRNA-seq. GH1-exo actions on protein synthesis, cAMP response, cell motility and metastases were assessed.

Results: NTA, exosomal marker detection, and GW4869 attenuated EV release, confirming the exosomal identity of pituitary EVs. Hydrocortisone increased exosome secretion in GH1 and GH3 cells, suggesting a stress-associated response. Exosomal RNA contents showed profiles distinct for pituitary cells, and rat primary hepatocytes exposed to GH1-exo exhibited transcriptomic alterations distinct from those elicited by GH or PRL. Intravenous GH1-exo injection into rats attenuated hepatic Eif2ak2 and Atf4 mRNA expression, both involved in cAMP responses and amino acid biosynthesis. GH1-exo suppressed protein synthesis and forskolin-induced cAMP levels in hepatocytes. GH1-exo treated HCT116 cells showed dysregulated p53 and MAPK pathways and attenuated motility of malignant HCT116 cells, and decreased tumor metastases in nude mice harboring splenic HCT116 implants.

Conclusions: Our findings elucidate biological actions of somatotroph-derived exosomes and implicate exosomes as non-hormonal pituitary-derived messengers.
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http://dx.doi.org/10.1210/clinem/dgab651DOI Listing
September 2021

Extracellular vesicles from immortalized cardiosphere-derived cells attenuate arrhythmogenic cardiomyopathy in desmoglein-2 mutant mice.

Eur Heart J 2021 09;42(35):3558-3571

Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, Los Angeles, CA 90048, USA.

Aims: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of β-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model.

Methods And Results: Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2mt/mt mice receiving EVs. DSG2mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs.

Conclusions: Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease.
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http://dx.doi.org/10.1093/eurheartj/ehab419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442111PMC
September 2021

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

J Heart Lung Transplant 2021 Nov 24;40(11):1387-1395. Epub 2021 Jun 24.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Extracellular vesicles (EVs) from heart stromal/progenitor cells modulate innate immunity, with salutary effects in a variety of cardiac disease models. Little is known, however, about the effects of these EVs on adaptive immunity.

Methods: Ex vivo differentiation of naïve CD4 T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (T) cells. These effects were further tested in vivo using the experimental autoimmune myocarditis (EAM) model.

Results: Using differentiated CD4 T cells, we show that EVs secreted by human-derived heart stromal/progenitor cells selectively influence the phenotype, activity, and proliferation of regulatory T (T) cells. Exposure of T cells to EVs results in faster proliferation, augmented production of IL-10, and polarization toward an intermediate FOXP3RORγt phenotype. In experimental autoimmune myocarditis, EVs attenuate cardiac inflammation and functional decline, in association with increased numbers of splenic IL10-T cells.

Conclusions: T cell modulation by EVs represents a novel therapeutic approach to inflammation, harnessing endogenous immunosuppressive mechanisms that may be applied in solid organ transplantation, graft-versus-host disease, and autoimmune disorders.
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http://dx.doi.org/10.1016/j.healun.2021.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570987PMC
November 2021

Delayed repolarization and ventricular tachycardia in patients with heart failure and preserved ejection fraction.

PLoS One 2021 13;16(7):e0254641. Epub 2021 Jul 13.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

Sudden death is the most common mode of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular arrhythmias (VA) have been suspected as the etiology but the supporting evidence in patients with HFpEF is scarce. We sought to investigate VA prevalence, and to determine if VA are associated with prolonged repolarization, in patients with HFpEF. In a retrospective case-control study design, Cedars-Sinai patients who underwent prolonged ambulatory electrocardiographic monitoring (Zio Patch) between 2016 and 2018 were screened for a clinical diagnosis of HFpEF. Patients with normal diastolic and systolic function who underwent Zio Patch monitoring were also reviewed as controls. Multivariable logistic regression was used to compare the prevalence of rhythm disturbances in patients with and without HFpEF. Ventricular tachycardia (VT) was more prevalent in patients with HFpEF (37% vs. 16% in controls, p = 0.001). Most episodes were non-sustained except for one case of sustained VT in a patient with HFpEF. Covariate-adjusted logistic regression including HFpEF diagnosis, age, sex, body mass index, and the presence of comorbidities revealed that only HFpEF was associated with increased risk of VT (relative risk 2.86, p = 0.023). Subgroup-analyses revealed an association between increased QTc interval and risk of VT (460 ± 38 ms in HFpEF patients with VT vs. 445 ± 28 ms in HFpEF patients without VT, p = 0.03). Non-sustained VT was more prevalent in patients with HFpEF compared to patients without HFpEF, and QTc interval prolongation was associated with VT in HFpEF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277017PMC
November 2021

Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial.

Open Heart 2021 07;8(2)

Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA

Background: Most cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.

Methods: In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised 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 months 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%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5% (4.0)) compared with 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).

Conclusions: In patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.

Trial Registration Number: NCT01458405.
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http://dx.doi.org/10.1136/openhrt-2021-001614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264869PMC
July 2021

Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice.

Mol Ther Nucleic Acids 2021 Jun 20;24:951-960. Epub 2021 Apr 20.

Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

Cardiosphere-derived cell exosomes (CDC) and YF1, a CDC-derived non-coding RNA, elicit therapeutic bioactivity in models of myocardial infarction and hypertensive hypertrophy. Here we tested the hypothesis that YF1, a 56-nucleotide Y RNA fragment, could alleviate cardiomyocyte hypertrophy, inflammation, and fibrosis associated with hypertrophic cardiomyopathy (HCM) in transgenic mice harboring a clinically relevant mutation in cardiac troponin I (cTnI). By quantitative PCR, YF1 was detectable in bone marrow, spleen, liver, and heart 30 min after intravenous (i.v.) infusion. For efficacy studies, mice were randomly allocated to receive i.v. YF1 or vehicle, monitored for ambulatory and cardiac function, and sacrificed at 4 weeks. YF1 (but not vehicle) improved ambulation and reduced cardiac hypertrophy and fibrosis. In parallel, peripheral mobilization of neutrophils and proinflammatory monocytes was decreased, and fewer macrophages infiltrated the heart. RNA-sequencing of macrophages revealed that YF1 confers substantive and broad changes in gene expression, modulating pathways associated with immunological disease and inflammatory responses. Together, these data demonstrate that YF1 can reverse hypertrophic and fibrotic signaling pathways associated with HCM, while improving function, raising the prospect that YF1 may be a viable novel therapeutic candidate for HCM.
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http://dx.doi.org/10.1016/j.omtn.2021.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141670PMC
June 2021

Pathogenesis of arrhythmogenic cardiomyopathy: role of inflammation.

Basic Res Cardiol 2021 06 4;116(1):39. Epub 2021 Jun 4.

Cedars-Sinai Medical Center, Smidt Heart Institute, 127 S. San Vicente Blvd., Los Angeles, CA, 90048, USA.

Arrhythmogenic cardiomyopathy (AC) is an inherited disease characterized by progressive breakdown of heart muscle, myocardial tissue death, and fibrofatty replacement. In most cases of AC, the primary lesion occurs in one of the genes encoding desmosomal proteins, disruption of which increases membrane fragility at the intercalated disc. Disrupted, exposed desmosomal proteins also serve as epitopes that can trigger an autoimmune reaction. Damage to cell membranes and autoimmunity provoke myocardial inflammation, a key feature in early stages of the disease. In several preclinical models, targeting inflammation has been shown to blunt disease progression, but translation to the clinic has been sparse. Here we review current understanding of inflammatory pathways and how they interact with injured tissue and the immune system in AC. We further discuss the potential role of immunomodulatory therapies in AC.
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http://dx.doi.org/10.1007/s00395-021-00877-5DOI Listing
June 2021

Cardiosphere-derived cells, with and without a biological scaffold, stimulate myogenesis and recovery of muscle function in mice with volumetric muscle loss.

Biomaterials 2021 07 27;274:120852. Epub 2021 Apr 27.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Electronic address:

Extremity trauma to military personnel and civilians commonly results in volumetric muscle loss (VML), leaving patients suffering chronic physical disability. Biomaterial-based technologies such as extracellular matrices (ECMs) are currently in clinical testing for soft tissue repair, but, in preclinical models of VML, the efficacy of ECMs is equivocal. In a murine model of VML, we investigated the effects of ECM and/or cardiosphere-derived cell (CDC) therapy; the latter improves skeletal myogenesis and muscle function in mdx mice, so we reasoned that CDCs may exert disease-modifying bioactivity in VML. While ECM alone improves functional recovery, CDCs have no additive or synergistic benefits with ECM transplantation following VML injury. However, CDCs alone are sufficient to promote muscle recovery, leading to sustained increases in muscle function throughout the study period. Notably, CDCs stimulate satellite cell accumulation in the muscle defect area and hasten myogenic progression (as evidenced by qPCR gene expression profiling), leading to global increases in myofiber numbers and anterior muscle compartment volume. Together, these data implicate CDCs as a viable therapeutic candidate to regenerate skeletal muscle injured by VML.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120852DOI Listing
July 2021

Mechanistic and therapeutic distinctions between cardiosphere-derived cell and mesenchymal stem cell extracellular vesicle non-coding RNA.

Sci Rep 2021 04 21;11(1):8666. Epub 2021 Apr 21.

Capricor Therapeutics, Inc., 8840 Wilshire Blvd., Beverly Hills, CA, 90211, USA.

Cell therapy limits ischemic injury following myocardial infarction (MI) by preventing cell death, modulating the immune response, and promoting tissue regeneration. The therapeutic efficacy of cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs) is associated with extracellular vesicle (EV) release. Prior head-to-head comparisons have shown CDCs to be more effective than MSCs in MI models. Despite differences in cell origin, it is unclear why EVs from different adult stem cell populations elicit differences in therapeutic efficacy. Here, we compare EVs derived from multiple human MSC and CDC donors using diverse in vitro and in vivo assays. EV membrane protein and non-coding RNA composition are highly specific to the parent cell type; for example, miR-10b is enriched in MSC-EVs relative to CDC-EVs, while Y RNA fragments follow the opposite pattern. CDC-EVs enhance the Arg1/Nos2 ratio in macrophages in vitro and reduce MI size more than MSC-EVs and suppress inflammation during acute peritonitis in vivo. Thus, CDC-EVs are distinct from MSC-EVs, confer immunomodulation, and protect the host against ischemic myocardial injury and acute inflammation.
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http://dx.doi.org/10.1038/s41598-021-87939-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060398PMC
April 2021

Electrocardiogram-less, free-breathing myocardial extracellular volume fraction mapping in small animals at high heart rates using motion-resolved cardiovascular magnetic reesonance multitasking: a feasibility study in a heart failure with preserved ejection fraction rat model.

J Cardiovasc Magn Reson 2021 02 11;23(1). Epub 2021 Feb 11.

Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Extracellular volume fraction (ECV) quantification with cardiovascular magnetic resonance (CMR) T mapping is a powerful tool for the characterization of focal or diffuse myocardial fibrosis. However, it is technically challenging to acquire high-quality T and ECV maps in small animals for preclinical research because of high heart rates and high respiration rates. In this work, we developed an electrocardiogram (ECG)-less, free-breathing ECV mapping method using motion-resolved CMR Multitasking on a 9.4 T small animal CMR system. The feasibility of characterizing diffuse myocardial fibrosis was tested in a rat heart failure model with preserved ejection fraction (HFpEF).

Methods: High-salt fed rats diagnosed with HFpEF (n = 9) and control rats (n = 9) were imaged with the proposed ECV Multitasking technique. A 25-min exam, including two 4-min T Multitasking scans before and after gadolinium injection, were performed on each rat. It allows a cardiac temporal resolution of 20 ms for a heart rate of ~ 300 bpm. Myocardial ECV was calculated from the hematocrit (HCT) and fitted T values of the myocardium and the blood pool. Masson's trichrome stain was used to measure the extent of fibrosis. Welch's t-test was performed between control and HFpEF groups.

Results: ECV was significantly higher in the HFpEF group (22.4% ± 2.5% vs. 18.0% ± 2.1%, P = 0.0010). A moderate correlation between the ECV and the extent of fibrosis was found (R = 0.59, P = 0.0098).

Conclusions: Motion-resolved ECV Multitasking CMR can quantify ECV in the rat myocardium at high heart rates without ECG triggering or respiratory gating. Elevated ECV found in the HFpEF group is consistent with previous human studies and well correlated with histological data. This technique has the potential to be a viable imaging tool for myocardial tissue characterization in small animal models.
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http://dx.doi.org/10.1186/s12968-020-00699-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877086PMC
February 2021

Casein-enhanced uptake and disease-modifying bioactivity of ingested extracellular vesicles.

J Extracell Vesicles 2021 01 11;10(3):e12045. Epub 2021 Jan 11.

Cedars-Sinai Medical Center Smidt Heart Institute Los Angeles California USA.

Extracellular vesicles (EVs) from cardiac stromal cells, developed as therapeutic candidates, improve dystrophic muscle function when administered parenterally, but oral delivery remains untested. We find that casein, the dominant protein in breast milk, enhances the uptake and bioactivity of ingested heart-derived EVs, altering gene expression in blood cells and enhancing muscle function in mice with muscular dystrophy. Thus, EVs, administered orally, are absorbed and exert disease-modifying bioactivity . Formulating EVs with casein enhances uptake and markedly expands the range of potential therapeutic applications.
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http://dx.doi.org/10.1002/jev2.12045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798403PMC
January 2021

Cardiac arrhythmias in hospitalized patients with COVID-19: A prospective observational study in the western United States.

PLoS One 2020 28;15(12):e0244533. Epub 2020 Dec 28.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

Arrhythmias have been reported frequently in COVID-19 patients, but the incidence and nature have not been well characterized. Patients admitted with COVID-19 and monitored by telemetry were prospectively enrolled in the study. Baseline characteristics, hospital course, treatment and complications were collected from the patients' medical records. Telemetry was monitored to detect the incidence of cardiac arrhythmias. The incidence and types of cardiac arrhythmias were analyzed and compared between survivors and non-survivors. Among 143 patients admitted with telemetry monitoring, overall in-hospital mortality was 25.2% (36/143 patients) during the period of observation (mean follow-up 23.7 days). Survivors were less tachycardic on initial presentation (heart rate 90.6 ± 19.6 vs. 99.3 ± 23.1 bpm, p = 0.030) and had lower troponin (peak troponin 0.03 vs. 0.18 ng/ml. p = 0.004), C-reactive protein (peak C-reactive protein 97 vs. 181 mg/dl, p = 0.029), and interleukin-6 levels (peak interleukin-6 30 vs. 246 pg/ml, p = 0.003). Sinus tachycardia, the most common arrhythmia (detected in 39.9% [57/143] of patients), occurred more frequently in non-survivors (58.3% vs. 33.6% in survivors, p = 0.009). Premature ventricular complexes occurred in 28.7% (41/143), and non-sustained ventricular tachycardia in 15.4% (22/143) of patients, with no difference between survivors and non-survivors. Sustained ventricular tachycardia and ventricular fibrillation were not frequent (seen only in 1.4% and 0.7% of patients, respectively). Contrary to reports from other regions, overall mortality was higher and ventricular arrhythmias were infrequent in this hospitalized and monitored COVID-19 population. Either disease or management-related factors could explain this divergence of clinical outcomes, and should be urgently investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244533PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769280PMC
January 2021

Small molecule inhibitors and culture conditions enhance therapeutic cell and EV potency via activation of beta-catenin and suppression of THY1.

Nanomedicine 2021 04 13;33:102347. Epub 2020 Dec 13.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Primary cell therapy continues to face significant hurdles to therapeutic translation including the inherent variations that exist from donor to donor, batch to batch, and scale-up driven modifications to the manufacturing process. Cardiosphere-derived cells (CDCs) are stromal/progenitor cells with clinically demonstrated tissue reparative capabilities. Mechanistic investigations have identified canonical Wnt/β-catenin signaling as a therapeutic potency marker, and THY1 (CD90) expression as inversely correlated with potency. Here we demonstrate that the cardiosphere formation process increases β-catenin levels and enriches for therapeutic miR content in the extracellular vesicles of these cells, namely miR-146a and miR-22. We further find that loss of potency is correlated with impaired cardiosphere formation. Finally, our data show that small GSK3β inhibitors including CHIR, and BIO and "pro-canonical Wnt" culturing conditions can rescue β-catenin signaling and reduce CD90 expression. These findings identify strategies that could be used to maintain CDC potency and therapeutic consistency.
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http://dx.doi.org/10.1016/j.nano.2020.102347DOI Listing
April 2021

Distinct features of calcium handling and β-adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction.

J Physiol 2020 11 9;598(22):5091-5108. Epub 2020 Sep 9.

Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, USA.

Key Points: Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for ∼50% of heart failure. Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF. We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation-contraction (EC) coupling. While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in β-adrenergic sensitivity. These differences in EC coupling and β-adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF.

Abstract: Heart failure with reduced or preserved ejection fraction (respectively, HFrEF and HFpEF) is the leading cause of death in developed countries. Although numerous therapies improve outcomes in HFrEF, there are no effective treatments for HFpEF. We studied phenotypically verified rat models of HFrEF and HFpEF to compare excitation-contraction (EC) coupling and protein expression in these two forms of heart failure. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Impaired diastolic relaxation and preserved ejection fraction were confirmed in each animal echocardiographically, and clinical signs of heart failure were documented. To generate HFrEF, Sprague-Dawley (SD) rats underwent permanent left anterior descending coronary artery ligation which, 8-10 weeks later, led to systolic dysfunction (verified echocardiographically) and clinical signs of heart failure. Calcium (Ca ) transients were measured in isolated cardiomyocytes under field stimulation or patch clamp. Ultra-high-speed laser scanning confocal imaging captured Ca sparks evoked by voltage steps. Western blotting and PCR were used to assay changes in EC coupling protein and RNA expression. Cardiomyocytes from rats with HFrEF exhibited impaired EC coupling, including decreased Ca transient (CaT) amplitude and defective couplon recruitment, associated with transverse (t)-tubule disruption. In stark contrast, HFpEF cardiomyocytes showed saturated EC coupling (increased I , high probability of couplon recruitment with greater Ca release synchrony, increased CaT) and preserved t-tubule integrity. β-Adrenergic stimulation of HFpEF myocytes with isoprenaline (isoproterenol) failed to elicit robust increases in I or CaT and relaxation kinetics. Fundamental differences in EC coupling distinguish HFrEF from HFpEF.
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http://dx.doi.org/10.1113/JP280425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693093PMC
November 2020

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

Eur Heart J 2020 09;41(36):3451-3458

Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

Aims: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.

Methods And Results: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.

Conclusion: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.

Trial Registration: Clinicaltrials.gov identifier: NCT01458405.
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http://dx.doi.org/10.1093/eurheartj/ehaa541DOI Listing
September 2020

Pre-existing traits associated with Covid-19 illness severity.

PLoS One 2020 23;15(7):e0236240. Epub 2020 Jul 23.

Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

Importance: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear.

Objective: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection.

Design: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation.

Setting: A large, multihospital healthcare system in Southern California.

Participants: All patients with confirmed Covid-19 infection (N = 442).

Results: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile.

Conclusions And Relevance: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236240PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377468PMC
August 2020

Quantitative Hybrid Cardiac [F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells.

Mol Ther Methods Clin Dev 2020 Sep 15;18:354-366. Epub 2020 Jun 15.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

Cardiosphere-derived cells (CDCs) are progenitor cells derived from heart tissue and have shown promising results in preclinical models. APOSEC, the secretome of irradiated peripheral blood mononuclear cells, has decreased infarct size in acute and chronic experimental myocardial infarction (MI). We enhanced the effect of CDCs with APOSEC preconditioning (apoCDC) and investigated the reparative effect in a translational pig model of reperfused MI. Supernatants of CDCs, assessed by proteomic analysis, revealed reduced production of extracellular matrix proteins after APOSEC preconditioning. In a porcine model of catheter-based reperfused anterior acute MI (AMI), CDCs with (apoCDC, n = 8) or without APOSEC preconditioning (CDC, n = 6) were infused intracoronary, 15 min after the start of reperfusion. Untreated AMI animals (n = 7) and sham procedures (n = 5) functioned as controls. 2-deoxy-2-(18 F)-fluoro-D-glucose-positron emission tomography-magnetic resonance imaging ([F]FDG-PET-MRI), with late enhancement after 1 month, showed reduced scar volume and lower transmurality of the infarcted area in CDC and apoCDC compared to AMI controls. Segmental quantitative PET images displayed indicated more residual viability in apoCDC. The left-ventricle (LV) ejection fraction was improved nonsignificantly to 45.8% ± 8.6% for apoCDC and 43.5% ± 7.1% for CDCs compared to 38.5% ± 4.4% for untreated AMI. Quantitative hybrid [F]FDG-PET-MRI demonstrated improved metabolic and functional recovery after CDC administration, whereas apoCDCs induced preservation of viability of the infarcted area.
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http://dx.doi.org/10.1016/j.omtm.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341058PMC
September 2020

Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis.

Front Physiol 2020 21;11:479. Epub 2020 May 21.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Heart disease remains an increasing major public health challenge in the United States and worldwide. A common end-organ feature in diseased hearts is myocardial fibrosis, which stiffens the heart and interferes with normal pump function, leading to pump failure. The development of cells for regenerative therapy has been met with many pitfalls on its path to clinical translation. Recognizing that regenerative cells secrete therapeutically bioactive vesicles has paved the way to circumvent many failures of cell therapy. In this review, we provide an overview of extracellular vesicles (EVs), with a focus on their utility as therapeutic agents for cardiac regeneration. We also highlight the engineering potential of EVs to enhance their therapeutic application.
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http://dx.doi.org/10.3389/fphys.2020.00479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255103PMC
May 2020

Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring.

J Am Heart Assoc 2020 06 28;9(12):e017144. Epub 2020 May 28.

The Smidt Heart Institute, Cedars-Sinai Health System Los Angeles CA.

Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 (COVID-19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID-19-positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs. We evaluated baseline and postmedication QT interval (corrected QT interval [QTc]; Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as follows: (1) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and (2) QTc increase of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID-19-positive/suspected patients, 314 (64%) received either/both drugs and 98 (73 COVID-19 positive and 25 suspected) met study criteria (age, 62±17 years; 61% men). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (=0.005) with medications. Significant prolongation was observed only in men (18±43 ms versus -0.2±28 ms in women; =0.02). A total of 12% of patients reached critical QTc prolongation. Changes in QTc were highest with the combination compared with either drug, with much greater prolongation with combination versus azithromycin (17±39 ms versus 0.5±40 ms; =0.07). No patients manifested torsades de pointes. Conclusions Overall, 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients should be carefully assessed.
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http://dx.doi.org/10.1161/JAHA.120.017144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429030PMC
June 2020

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series.

Basic Res Cardiol 2020 05 12;115(4):36. Epub 2020 May 12.

Cedars-Sinai Medical Center, Smidt Heart Institute, 127 S. San Vicente Boulevard, Advanced Health Sciences Pavilion, Third Floor, Suite A3100, Los Angeles, CA, 90048, USA.

There are no definitive therapies for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, new therapeutic strategies are needed to improve clinical outcomes, particularly in patients with severe disease. This case series explores the safety and effectiveness of intravenous allogeneic cardiosphere-derived cells (CDCs), formulated as CAP-1002, in critically ill patients with confirmed coronavirus disease 2019 (COVID-19). Adverse reactions to CAP-1002, clinical status on the World Health Organization (WHO) ordinal scale, and changes in pro-inflammatory biomarkers and leukocyte counts were analyzed. All patients (n = 6; age range 19-75 years, 1 female) required ventilatory support (invasive mechanical ventilation, n = 5) with PaO/FiO ranging from 69 to 198. No adverse events related to CAP-1002 administration were observed. Four patients (67%) were weaned from respiratory support and discharged from the hospital. One patient remains mechanically ventilated as of April 28th, 2020; all survive. A contemporaneous control group of critically ill COVID-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization. Ferritin was elevated in all patients at baseline (range of all patients 605.43-2991.52 ng/ml) and decreased in 5/6 patients (range of all patients 252.89-1029.90 ng/ml). Absolute lymphocyte counts were low in 5/6 patients at baseline (range 0.26-0.82 × 10/µl) but had increased in three of these five patients at last follow-up (range 0.23-1.02 × 10/µl). In this series of six critically ill COVID-19 patients, intravenous infusion of CAP-1002 was well tolerated and associated with resolution of critical illness in 4 patients. This series demonstrates the apparent safety of CAP-1002 in COVID-19. While this initial experience is promising, efficacy will need to be further assessed in a randomized controlled trial.
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http://dx.doi.org/10.1007/s00395-020-0795-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214858PMC
May 2020

COVID-19 and the Heart.

Circ Res 2020 05 7;126(10):1443-1455. Epub 2020 Apr 7.

From the Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Infection with the severe acute respiratory syndrome novel coronavirus produces a clinical syndrome known as 2019 novel coronavirus disease (COVID-19). When severe, COVID-19 is a systemic illness characterized by hyperinflammation, cytokine storm, and elevations of cardiac injury biomarkers. Here, we review what is known about the pathophysiology of COVID-19, its cardiovascular manifestations, and emerging therapeutic prospects. In this rapidly moving field, this review was comprehensive as of April 3, 2020.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317055DOI Listing
May 2020

Mechanisms of atrial fibrillation in aged rats with heart failure with preserved ejection fraction.

Heart Rhythm 2020 06 15;17(6):1025-1033. Epub 2020 Feb 15.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Although ∼20% of the elderly population develops atrial fibrillation (AF), little is known about the mechanisms. Heart failure with preserved ejection fraction (HFpEF), which is associated with AF, is more common in aged women than in men.

Objective: The purpose of this study was to identify potential mechanisms of AF in an age-related HFpEF model.

Methods: In aged female Fischer F344 rats (21- to 24-month-old), which are prone to HFpEF, we induced AF by atrial pacing. Young Fischer F344 female rats (3- to 4-month-old) and age-matched Sprague Dawley female rats (27-month-old) served as controls. Phenotyping included echocardiography to assess left ventricular structure/function; in vivo electrophysiology and ex vivo high-resolution optical mapping to assess AF vulnerability; systemic and atrial inflammatory profiling; atrial histology; and expression of inflammasome signaling proteins.

Results: Aged rats developed left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, and pulmonary congestion, without ejection fraction impairment, thus meeting the criteria for HFpEF. Increased serum inflammatory markers, hypertension, and obesity further characterize aged females. Sinoatrial and atrioventricular node dysfunction was associated with the high inducibility of AF in aged rats. Ex vivo electrical activation mapping revealed abnormal β-adrenergic responsiveness and slowed conduction velocity. Atrial inflammasome signaling was enhanced in aged rats, which may contribute to fibrotic remodeling and high AF susceptibility.

Conclusion: Together, our data demonstrate that aging-related atrial remodeling and HFpEF are associated with atrial enlargement, fibrosis, conduction abnormalities, and nodal dysfunction, favoring a substrate conducive to AF.
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http://dx.doi.org/10.1016/j.hrthm.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802887PMC
June 2020

Direct and Indirect Suppression of Scn5a Gene Expression Mediates Cardiac Na Channel Inhibition by Wnt Signalling.

Can J Cardiol 2020 04 3;36(4):564-576. Epub 2019 Oct 3.

University of Ottawa Heart Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Background: Myocardial infarction and heart failure are associated with reduced voltage-gated Na current (I) that promotes arrhythmias and sudden deaths. We have previously shown that the Wnt/β-catenin signalling (Wnt signalling), which is active in heart disease, reduces cardiac I, suggesting that Wnt signalling may be a potential therapeutic target. However, because Wnt signalling is required for the homeostasis of many noncardiac tissues, administration of Wnt inhibitors to heart patients would cause significant side effects. The present study aims to elucidate the molecular mechanisms of cardiac I inhibition by Wnt, which would identify cardiac-specific therapeutic targets.

Methods: Wnt signalling was activated in neonatal rat ventricular myocytes by Wnt3a protein. Adenovirus expressing Wnt3a was injected into the adult rat ventricle. CRISPR/Cas9 and chromatin immunoprecipitation were used for mechanistic studies.

Results: Wnt signalling activation in neonatal rat ventricular myocytes reduced Na1.5 protein and Scn5a mRNA, but increased Tbx3, a known suppressor of Scn5a. Chromatin immunoprecipitation showed that Wnt signalling inhibits Scn5a expression through downstream mediator (TCF4) binding to both Tbx3 and Scn5a promoters. Overexpression or knockdown of Tbx3 directly modified Na1.5 and I, whereas CRISPR/Cas9-induced mutations at TCF4 binding sites within the Scn5a promoter attenuated Wnt inhibition of Scn5a and Na1.5. In adult rat hearts, adenovirus expressing Wnt3a reduced Na1.5, increased QRS duration in electrocardiogram, and increased the susceptibility to ventricular tachycardia.

Conclusions: Wnt signalling inhibits the Na channel by direct and indirect (via Tbx3) suppression of Scn5a transcription. Strategies to block TCF4 binding to the Tbx3 and Scn5a promoters would represent novel strategies for cardiac-specific inhibition of the Wnt pathway to rescue I and prevent sudden cardiac deaths.
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http://dx.doi.org/10.1016/j.cjca.2019.09.019DOI Listing
April 2020

Allogeneic cardiosphere-derived cells for the treatment of heart failure with reduced ejection fraction: the Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial.

EuroIntervention 2020 Jul 17;16(4):e293-e300. Epub 2020 Jul 17.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Aims: The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial.

Methods And Results: We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial. Intracoronary catheterisation delivered four escalating doses (totalling 37.5-75 million cells) by sequential non-occlusive technique to all three major coronary arteries. The primary safety endpoint was a composite of post-infusion TIMI flow, ventricular tachycardia/fibrillation, sudden death, major adverse cardiac events or acute myocarditis within 72 hours. Twelve patients were male and EF averaged 23.0% (±4.5%). No primary safety endpoints were observed. Two patients died of HFrEF progression nine and 12 months following infusion. Compared to baseline, there was an improvement in EF (26.8% vs 22.9%, p=0.023) and left ventricular end-systolic volume (139.5 vs 177.8 cm3, p=0.03) at six months. Quality of life (QoL) scores and NYHA class (p=0.006) improved at six months. At 12 months, the improvement in EF and QoL remained significant.

Conclusions: Global intracoronary infusion of allogeneic CDCs is safe and feasible. The efficacy of allogeneic CDCs in HFrEF needs to be tested in larger randomised trials.
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http://dx.doi.org/10.4244/EIJ-D-19-00035DOI Listing
July 2020
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