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Stereotactic body radiation therapy (SBRT) is an innovative modality for treatment of refractory ventricular arrhythmias (VA). Phase I/II clinical trials have demonstrated the remarkable efficacy of SBRT at reducing VA burden(by>85%) in patients with good short-term safety. SBRT as an option for VA treatment delivered in an ambulatory, non-sedated patient in a single fraction, during an outpatient session of 15-30 minutes, without added risks of anesthetic or surgery is clinically relevant. However, the underlying mechanism remains unclear. Currently used clinical dosing of SBRT has been derived from preclinical studies aimed to induce transmural fibrosis in the atria. The propitious clinical effects of SBRT appear earlier than the time-course for fibrosis. This review addresses the plausible mechanisms by which radiation alters the electrophysiological properties of myocytes and myocardial conduction to impart an anti-arrhythmic effect to elucidate clinical observations and point the direction for further research in this promising area.
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BACKGROUND: Cardiac magnetic resonance imaging (CMR)-defined ventricular scar and anatomic conduction channels (CMR-CCs) offer promise in delineating ventricular tachycardia substrate. No studies have validated channels with coregistered histology, nor have they ascertained the histological characteristics of deceleration zones (DZs) within these channels. We aimed to validate CMR scar and CMR-CCs with whole-heart histology and electroanatomic mapping in a postinfarction model. METHODS: Five sheep underwent anteroseptal infarction. CMR (116±20 days post infarct) was postprocessed using ADAS-3-dimensional, varying pixel intensity thresholds (5545, 6040, 6535, and 7030). DZs were identified by electroanatomic mapping (129±12 days post infarct). Explanted hearts were sectioned and stained with Picrosirius red, and whole-heart histopathologic shells were generated. Scar topography as well as percentage fibrosis, adiposity, and remaining viable myocardium within 3 mm histological biopsies and within CMR-CCs were determined. RESULTS: Using the standard 6040 thresholding, CMR had 83.8% accuracy for identifying histological scar in the endocardium (κ, 0.666) and 61.4% in the epicardium (κ, 0.276). Thirty-seven CMR-CCs were identified by varying thresholding; 23 (62%) were unique. DZs colocalized to 19 of 23 (83%) CMR-CCs. Twenty (87%) CMR-CCs were histologically confirmed. Within-channel histological fibrosis did not differ by the presence of DZs (P=0.242). Within-channel histological adiposity was significantly higher at sites with versus without DZs (24.1% versus 8.3%; P<0.001). CONCLUSIONS: Postprocessed CMR-derived scars and channels were validated by histology and electroanatomic mapping. Regions of CMR-CCs at sites of DZs had higher adiposity but similar fibrosis than regions without DZs, suggesting that lipomatous metaplasia may contribute to arrhythmogenicity of postinfarction scar.
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Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90-CD200+ and SIRPA+CD90-CD200-, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.
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Arritmias Cardíacas , Miócitos Cardíacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/transplante , Animais , Arritmias Cardíacas/terapia , Humanos , Modelos Animais de Doenças , Infarto do Miocárdio/terapia , Suínos , Células Cultivadas , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/transplante , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos dos fármacos , Fenótipo , Biomarcadores/metabolismo , Células-Tronco Pluripotentes/transplante , Transplante de Células-Tronco/métodos , Antiarrítmicos/uso terapêutico , Antiarrítmicos/farmacologia , Frequência Cardíaca/fisiologiaRESUMO
BACKGROUND: The evolution of myocardial scar and its arrhythmogenic potential postinfarct is incompletely understood. OBJECTIVES: This study sought to investigate scar and border zone (BZ) channels evolution in an animal ischemia-reperfusion injury model using late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). METHODS: Five swine underwent 90-minute balloon occlusion of the mid-left anterior descending artery, followed by LGE-CMR at day (d) 3, d30, and d58 postinfarct. Invasive electroanatomic mapping (EAM) was performed at 2 months. Topographical reconstructions of LGE-CMR were analyzed for left ventricular core and BZ scar, BZ channel geometry, and complexity, including transmurality, orientation, and number of entrances/exits. RESULTS: LVEF reduced from 48.0% ± 1.8% to 41.3% ± 2.3% postinfarct. Total scar mass reduced over time (P = 0.008), including BZ (P = 0.002) and core scar (P = 0.05). A total of 72 BZ channels were analyzed across all animals and timepoints. Channel length (P = 0.05) and complexity (P = 0.02) reduced progressively from d3 to d58. However, at d58, 64% of channels were newly formed and 36% were midmyocardial. Conserved channels were initially longer and more complex. All LGE-CMR channels colocalized to regions of maximal decrement on EAM, with significantly greater decrement (115 ± 31 ms vs 83 ± 29 ms; P < 0.001) and uncovering of split potentials (24.8% vs 2.6%; P < 0.001) within channels. In total, 3 of 5 animals had inducible VT and tended to have more channels with greater midmyocardial involvement and functional decrement than those without VT. CONCLUSIONS: BZ channels form early postinfarct and demonstrate evolutionary complexity and functional conduction slowing on EAM, highlighting their arrhythmogenic potential. Some channels regress in complexity and length, but new channels form at 2 months' postinfarct, which may be midmyocardial, reflecting an evolving, 3-dimensional substrate for VT. LGE-CMR may help identify BZ channels that may support VT early postinfarct and lead to sudden death.
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Single-cell technology has allowed researchers to probe tissue complexity and dynamics at unprecedented depth in health and disease. However, the generation of high-dimensionality single-cell atlases and virtual three-dimensional tissues requires integrated reference maps that harmonize disparate experimental designs, analytical pipelines, and taxonomies. Here, we present a comprehensive single-cell transcriptome integration map of cardiac fibrosis, which underpins pathophysiology in most cardiovascular diseases. Our findings reveal similarity between cardiac fibroblast (CF) identities and dynamics in ischemic versus pressure overload models of cardiomyopathy. We also describe timelines for commitment of activated CFs to proliferation and myofibrogenesis, profibrotic and antifibrotic polarization of myofibroblasts and matrifibrocytes, and CF conservation across mouse and human healthy and diseased hearts. These insights have the potential to inform knowledge-based therapies.
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Fibroblastos , Fibrose , Análise de Célula Única , Transcriptoma , Animais , Análise de Célula Única/métodos , Humanos , Fibroblastos/metabolismo , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Perfilação da Expressão GênicaRESUMO
Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.
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Modelos Animais de Doenças , Infarto do Miocárdio , Animais , Feminino , Suínos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Função Ventricular Esquerda/fisiologia , Volume Sistólico/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodosRESUMO
Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.
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Cardiotoxicidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Miócitos Cardíacos , Humanos , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Células HEK293 , Doxorrubicina/farmacologiaRESUMO
BACKGROUND: To analyze the admission and treatment process of potentially COVID-19-infected patients in the intensive care unit under normalization, prevention, and control of the pandemic. METHODS: A multidisciplinary team was assembled to develop a flowchart of potentially COVID-19-infected patients admitted to the intensive care unit and identify potential failure steps and modes throughout the process using the failure mode and effect analysis method. Through risk priority number (RPN) analysis of each failure mode, those with the highest impact on nosocomial infection were identified, and the priority of implementation was determined. Related corrective measures have been developed to continuously improve clinical practice and management. RESULTS: Eighty potential failure modes were identified, and 8 potential failure modes were identified with RPNs greater than 100. These high RPNs of the failure modes were associated with careless inquiries of epidemiological histories by nurses, inadequate implementation of management standards by nursing assistants, and exposure of attending physicians to potentially risky environments. Finally, 18 general corrective measures are proposed. CONCLUSIONS: Application of the failure mode and effect analysis method for quality improvement is a powerful tool for predicting potential failures in the process and can suggest corrective measures that could help avoid nosocomial infection during a pandemic.
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Background: Inducible ventricular tachycardia (VT) at electrophysiology study (EPS) predicts sudden cardiac death because of ventricular tachyarrhythmia, the single greatest cause of death within 2 years after myocardial infarction (MI). Objectives: We aimed to assess the association between standard modifiable risk factors (SMuRFs) and inducible VT at EPS early after MI. Methods: Consecutive patients with left ventricle ejection fraction ≤40% on days 3-5 after ST elevation MI (STEMI) who underwent EPS were prospectively recruited. Positive EPS was defined as induced sustained monomorphic VT cycle length ≥200â ms for ≥10â s or shorter if hemodynamically compromised. The primary outcome was inducibility of VT at EPS, and the secondary outcome was all-cause mortality on follow-up. Results: In 410 eligible patients undergoing EPS soon (median of 9 days) after STEMI, 126 had inducible VT. Ex-smokers experienced an increased risk of inducible VT [multivariable logistic regression adjusted odds ratio (OR) 2.0, p = 0.033] compared with current or never-smokers, with comparable risk. The presence of any SMuRFs apart from being a current smoker conferred an increased risk of inducible VT (adjusted OR 1.9, p = 0.043). Neither the number of SMuRFs nor the presence of any SMuRFs was associated with mortality at a median follow-up of 5.4 years. Conclusions: In patients with recent STEMI and impaired left ventricular function, the presence of any SMuRFs, apart from being a current smoker, conferred an increased risk of inducible VT at EPS. These results highlight the need to modify SMuRFs in this high-risk subset of patients.
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[This corrects the article DOI: 10.3389/fpsyt.2021.687615.].
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AIM: Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of myocardial infarction. We aimed to investigate SCAD survivors' perceptions of their quality-of-care and its relationship to quality-of-life. METHODS AND RESULTS: An anonymous survey was distributed online to SCAD survivors involved in Australian SCAD support groups, with 172 (95.3% female, mean age 52.6 ± 9.2 years) participants in the study. The survey involved assessment of quality-of-life using a standardised questionnaire (EQ-5DTM-3L). Respondents rated the quality-of-care received during their hospital admission for SCAD a median 8/10 [interquartile range (IQR) 7-10]. Respondents ≤50 years versus >50 years were more likely to perceive that their symptoms were not treated seriously as a myocardial infarction (χ2 = 4.127, df = 1, p < 0.05). Participants rated clinician's knowledge of SCAD a median 4/10 (IQR 2-8) and 7/10 (IQR 3-9) for Emergency and Cardiology clinicians, respectively (p < 0.05). The internet was the most selected source (45.4%) of useful SCAD information. The mean EQ-5DTM summary index was 0.79 (population norm 0.87). 47.2% of respondents reported a mental health condition diagnosis, with 36% of these diagnosed after their admission with SCAD. Quality-of-life was significantly associated with perceived quality-of-care: EQ-5DTM index/(1-EQ-5DTM index) increased by 13% for each unit increase in quality-of-care after adjusting for age and comorbidities (p < 0.001). CONCLUSION: While SCAD survivors rated their overall hospital care highly, healthcare providers' knowledge of SCAD was perceived to be poor and, the most common source of SCAD information was the internet. Mental health conditions were common, and a significant association was observed between perceived quality-of-care and SCAD survivors' quality-of-life.
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Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed.
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Aterosclerose , Doença da Artéria Coronariana , Infarto do Miocárdio , Humanos , Doença da Artéria Coronariana/epidemiologia , Procedimentos Clínicos , Fatores de Risco de Doenças CardíacasRESUMO
Recombinant adeno-associated viruses (rAAVs) have emerged as one of the most promising gene therapy vectors that have been successfully used in pre-clinical models of heart disease. However, this has not translated well to humans due to species differences in rAAV transduction efficiency. As a result, the search for human cardiotropic capsids is a major contemporary challenge. We used a capsid-shuffled rAAV library to perform directed evolution in human iPSC-derived cardiomyocytes (hiPSC-CMs). Five candidates emerged, with four presenting high sequence identity to AAV6, while a fifth divergent variant was related to AAV3b. Functional analysis of the variants was performed in vitro using hiPSC-CMs, cardiac organoids, human cardiac slices, non-human primate and porcine cardiac slices, as well as mouse heart and liver in vivo. We showed that cell entry was not the best predictor of transgene expression efficiency. The novel variant rAAV.KK04 was the best-performing vector in human-based screening platforms, exceeding the benchmark rAAV6. None of the novel capsids demonstrate a significant transduction of liver in vivo. The range of experimental models used revealed the value of testing for tropism differences under the conditions of human specificity, bona fide, myocardium and cell type of interest.
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Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.
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Proteínas da Matriz Extracelular , Insuficiência Cardíaca , Ruptura Cardíaca , Infarto do Miocárdio , Animais , Humanos , Camundongos , Coração , Insuficiência Cardíaca/genética , Ruptura Cardíaca/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Proteínas da Matriz Extracelular/genéticaRESUMO
AIMS: This study assessed associations of minimum final extrastimulus coupling interval utilized within electrophysiology study (EPS) after myocardial infarction (MI) and possible site of origin of induced ventricular tachycardia (VT) with long-term occurrence of spontaneous ventricular tachyarrhythmia and long-term survival. METHODS AND RESULTS: This prospective study recruited consecutive patients with left ventricular ejection fraction (LVEF) ≤ 40% who underwent EPS days 3-5 after MI between 2004 and 2017. Positive EPS was defined as sustained monomorphic VT cycle length ≥200â ms for ≥10â s or shorter duration if haemodynamic compromise occurred. Each of the four extrastimuli was shortened by 10â ms at a time, until it failed to capture the ventricle (ventricular refractoriness) or induced ventricular tachyarrhythmia. Outcomes included spontaneous ventricular tachyarrhythmia occurrence and all-cause mortality. Shorter coupling interval length of final extrastimulus that induced VT was associated with higher risk of spontaneous ventricular tachyarrhythmia (P < 0.001). Significantly higher rates of spontaneous ventricular tachyarrhythmia (65.2% vs. 23.2%; P < 0.001) were observed for final coupling interval at EPS <200â ms vs. >200â ms. Right bundle branch block (RBBB) morphology of induced VT, with possible site of origin from the left ventricle, was associated with all-cause mortality [hazard ratio (HR) 3.2, P = 0.044] and a composite of spontaneous ventricular tachyarrhythmia recurrence or mortality (HR 1.8, P = 0.043). CONCLUSION: Ventricular tachycardia induced with shorter coupling intervals was associated with higher risk of spontaneous ventricular tachyarrhythymia on follow-up, indicating that the final extrastimulus coupling interval at EPS early after MI should be determined by ventricular refractoriness. Induced VT with possible origin from left ventricle was associated with increased risk of spontaneous ventricular tachyarrhythmia recurrence or death.
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Desfibriladores Implantáveis , Infarto do Miocárdio , Taquicardia Ventricular , Humanos , Volume Sistólico/fisiologia , Função Ventricular Esquerda , Estudos Prospectivos , Desfibriladores Implantáveis/efeitos adversos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Eletrofisiologia Cardíaca , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/prevenção & controle , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/epidemiologia , SeguimentosRESUMO
Introduction: Heart failure due to myocardial infarction is a progressive and debilitating condition, affecting millions worldwide. Novel treatment strategies are desperately needed to minimise cardiomyocyte damage after myocardial infarction and to promote repair and regeneration of the injured heart muscle. Plasma polymerized nanoparticles (PPN) are a new class of nanocarriers which allow for a facile, one-step functionalization with molecular cargo. Methods: Here, we conjugated platelet-derived growth factor AB (PDGF-AB) to PPN, engineering a stable nano-formulation, as demonstrated by optimal hydrodynamic parameters, including hydrodynamic size distribution, polydisperse index (PDI) and zeta potential, and further demonstrated safety and bioactivity in vitro and in vivo. We delivered PPN-PDGF-AB to human cardiac cells and directly to the injured rodent heart. Results: We found no evidence of cytotoxicity after delivery of PPN or PPN-PDGFAB to cardiomyocytes in vitro, as determined through viability and mitochondrial membrane potential assays. We then measured contractile amplitude of human stem cell derived cardiomyocytes and found no detrimental effect of PPN on cardiomyocyte contractility. We also confirmed that PDGF-AB remains functional when bound to PPN, with PDGF receptor alpha positive human coronary artery vascular smooth muscle cells and cardiac fibroblasts demonstrating migratory and phenotypic responses to PPN-PDGF-AB in the same manner as to unbound PDGF-AB. In our rodent model of PPN-PDGF-AB treatment after myocardial infarction, we found a modest improvement in cardiac function in PPN-PDGF-AB treated hearts compared to those treated with PPN, although this was not accompanied by changes in infarct scar size, scar composition, or border zone vessel density. Discussion: These results demonstrate safety and feasibility of the PPN platform for delivery of therapeutics directly to the myocardium. Future work will optimize PPN-PDGF-AB formulations for systemic delivery, including effective dosage and timing to enhance efficacy and bioavailability, and ultimately improve the therapeutic benefits of PDGF-AB in the treatment of heart failure cause by myocardial infarction.
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After myocardial infarction (MI), fibroblasts progress from proliferative to myofibroblast states, resulting in fibrosis. Platelet-derived growth factors (PDGFs) are reported to induce fibroblast proliferation, myofibroblast differentiation, and fibrosis. However, we have previously shown that PDGFs improve heart function post-MI without increasing fibrosis. We treated human cardiac fibroblasts with PDGF isoforms then performed RNA sequencing to show that PDGFs reduced cardiac fibroblasts myofibroblast differentiation and downregulated cell cycle pathways. Using mouse/pig MI models, we reveal that PDGF-AB infusion increases cell-cell interactions, reduces myofibroblast differentiation, does not affect proliferation, and accelerates scar formation. RNA sequencing of pig hearts after MI showed that PDGF-AB reduces inflammatory cytokines and alters both transcript variants and long noncoding RNA expression in cell cycle pathways. We propose that PDGF-AB could be used therapeutically to manipulate post-MI scar maturation with subsequent beneficial effects on cardiac function.
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Ischaemic heart disease is the primary cause of death worldwide with myocardial infarction (MI) contributing to significant morbidity and mortality. The human heart has a limited capacity to regenerate and the significant loss of cardiomyocytes after MI can overwhelm this limited innate regenerative capability. This is in part compensated for by the creation of collagen-rich scar tissue. Therapeutic angiogenesis is an exciting prospect that can assist cardiac regeneration after MI with various approaches having been explored. This review will focus on results from clinical growth factor trials, and the lack of clinical translation. Inconsistencies in results from these may be due to heterogeneity within patient selection and an incomplete understanding of therapeutic differences between isoforms of active agents. The technology used has also evolved with recombinant protein and, subsequently, gene therapy being utilised. Innovative therapeutic designs, such as combinatorial therapies, might help to resolve these issues in the future.