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Nature Communications Sep 2023Cardiogenic growth factors play important roles in heart development. Placental growth factor (PLGF) has previously been reported to have angiogenic effects; however,...
Cardiogenic growth factors play important roles in heart development. Placental growth factor (PLGF) has previously been reported to have angiogenic effects; however, its potential role in cardiogenesis has not yet been determined. We analyze single-cell RNA-sequencing data derived from human and primate embryonic hearts and find PLGF shows a biphasic expression pattern, as it is expressed specifically on ISL1 second heart field progenitors at an earlier stage and on vascular smooth muscle cells (SMCs) and endothelial cells (ECs) at later stages. Using chemically modified mRNAs (modRNAs), we generate a panel of cardiogenic growth factors and test their effects on enhancing cardiomyocyte (CM) and EC induction during different stages of human embryonic stem cell (hESC) differentiations. We discover that only the application of PLGF modRNA at early time points of hESC-CM differentiation can increase both CM and EC production. Conversely, genetic deletion of PLGF reduces generation of CMs, SMCs and ECs in vitro. We also confirm in vivo beneficial effects of PLGF modRNA for development of human heart progenitor-derived cardiac muscle grafts on murine kidney capsules. Further, we identify the previously unrecognized PLGF-related transcriptional networks driven by EOMES and SOX17. These results shed light on the dual cardiomyogenic and vasculogenic effects of PLGF during heart development.
Topics: Female; Humans; Animals; Mice; Placenta Growth Factor; Endothelial Cells; Myocardium; Myocytes, Cardiac; Cell Differentiation
PubMed: 37669989
DOI: 10.1038/s41467-023-41305-7 -
Computers in Biology and Medicine Oct 2023Accurate myocardial segmentation is crucial for the diagnosis of various heart diseases. However, segmentation results often suffer from topology structural errors, such...
Accurate myocardial segmentation is crucial for the diagnosis of various heart diseases. However, segmentation results often suffer from topology structural errors, such as broken connections and holes, especially in cases of poor image quality. These errors are unacceptable in clinical diagnosis. We proposed a Topology-Sensitive Weight (TSW) model to keep both pixel-wise accuracy and topological correctness. Specifically, the Position Weighting Update (PWU) strategy with the Boundary-Sensitive Topology (BST) module can guide the model to focus on positions where topological features are sensitive to pixel values. The Myocardial Integrity Topology (MIT) module can serve as a guide for maintaining myocardial integrity. We evaluate the TSW model on the CAMUS dataset and a private echocardiography myocardial segmentation dataset. The qualitative and quantitative experimental results show that the TSW model significantly enhances topological accuracy while maintaining pixel-wise precision.
Topics: Humans; Algorithms; Image Processing, Computer-Assisted; Myocardium; Heart Diseases; Echocardiography
PubMed: 37633088
DOI: 10.1016/j.compbiomed.2023.107286 -
Circulation Research Jun 2024The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in... (Review)
Review
The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.
Topics: Humans; Myocardial Infarction; Animals; Signal Transduction; Regeneration; Inflammation Mediators; Myocardium
PubMed: 38843294
DOI: 10.1161/CIRCRESAHA.124.323658 -
Pharmacological Research Jul 2024Inflammation is a crucial factor in cardiac remodeling after acute myocardial infarction (MI). Neutrophils, as the first wave of leukocytes to infiltrate the injured... (Review)
Review
Inflammation is a crucial factor in cardiac remodeling after acute myocardial infarction (MI). Neutrophils, as the first wave of leukocytes to infiltrate the injured myocardium, exacerbate inflammation and cardiac injury. However, therapies that deplete neutrophils to manage cardiac remodeling after MI have not consistently produced promising outcomes. Recent studies have revealed that neutrophils at different time points and locations may have distinct functions. Thus, transferring neutrophil phenotypes, rather than simply blocking their activities, potentially meet the needs of cardiac repair. In this review, we focus on discussing the fate, heterogeneity, functions of neutrophils, and attempt to provide a more comprehensive understanding of their roles and targeting strategies in MI. We highlight the strategies and translational potential of targeting neutrophils to limit cardiac injury to reduce morbidity and mortality from MI.
Topics: Humans; Myocardial Infarction; Neutrophils; Animals; Myocardium
PubMed: 38866263
DOI: 10.1016/j.phrs.2024.107256 -
Scientific Reports Aug 2023The aim of this paper is to introduce a new mathematical model that simulates myocardial blood perfusion that accounts for multiscale and multiphysics features. Our...
The aim of this paper is to introduce a new mathematical model that simulates myocardial blood perfusion that accounts for multiscale and multiphysics features. Our model incorporates cardiac electrophysiology, active and passive mechanics, hemodynamics, valve modeling, and a multicompartment Darcy model of perfusion. We consider a fully coupled electromechanical model of the left heart that provides input for a fully coupled Navier-Stokes-Darcy Model for myocardial perfusion. The fluid dynamics problem is modeled in a left heart geometry that includes large epicardial coronaries, while the multicompartment Darcy model is set in a biventricular myocardium. Using a realistic and detailed cardiac geometry, our simulations demonstrate the biophysical fidelity of our model in describing cardiac perfusion. Specifically, we successfully validate the model reliability by comparing in-silico coronary flow rates and average myocardial blood flow with clinically established values ranges reported in relevant literature. Additionally, we investigate the impact of a regurgitant aortic valve on myocardial perfusion, and our results indicate a reduction in myocardial perfusion due to blood flow taken away by the left ventricle during diastole. To the best of our knowledge, our work represents the first instance where electromechanics, hemodynamics, and perfusion are integrated into a single computational framework.
Topics: Reproducibility of Results; Perfusion; Heart; Myocardium; Heart Ventricles
PubMed: 37648701
DOI: 10.1038/s41598-023-41312-0 -
Chinese Medical Journal Oct 2023Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca 2+ homeostasis. The present study aimed to investigate the mechanism...
BACKGROUND
Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca 2+ homeostasis. The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation (small ubiquitin-like modifier) process after ischemia/reperfusion injury (I/RI) in vitro and in vivo .
METHODS
Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout (KO) and wild-type mice with I/RI were compared. SUMO-relevant protein expression and localization were detected by quantitative real-time PCR (RT-qPCR), Western blotting, and immunofluorescence in vitro and in vivo . Serca2a-SUMOylation, infarct size, and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes, were detected by immunoprecipitation, triphenyltetrazolium chloride (TTC)-Evans blue staining, and echocardiography respectively.
RESULTS
The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO + I/RI groups. Senp1 and Senp2 messenger ribose nucleic acid (mRNA) and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI. However, the highest levels in HL-1 cells were recorded at 12 h. Senp2 expression increased in the cytoplasm, unlike that of Senp1. Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline, reduced the infarction area, and improved cardiac function, while inhibition of Senp1 protein could not restore the above indicators.
CONCLUSION
I/RI activated Senp1 and Senp2 protein expression, which promoted Serca2a-deSUMOylation, while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.
Topics: Animals; Mice; Calcium; Cysteine Endopeptidases; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Proteins; Sarcoplasmic Reticulum Calcium-Transporting ATPases
PubMed: 37462038
DOI: 10.1097/CM9.0000000000002757 -
Kidney360 Nov 2023Myocardial fibrosis in hearts from patients with CKD is characterized by increased trimeric tensile collagen type I and decreased elastic collagen type III compared with...
KEY POINTS
Myocardial fibrosis in hearts from patients with CKD is characterized by increased trimeric tensile collagen type I and decreased elastic collagen type III compared with hearts from hypertensive or healthy donors, suggesting a unique fibrotic phenotype. Myocardial fibrosis in CKD is driven by alterations in extracellular matrix proteostasis, including dysregulation of metalloproteinases and cross-linking enzymes. CKD-associated mineral stressors uniquely induce a fibronectin-independent mechanism of fibrillogenesis characterized by formation of trimeric collagen compared with proinflammatory/fibrotic cytokines.
BACKGROUND
Myocardial fibrosis is a major life-limiting problem in CKD. Despite this, the molecular phenotype and metabolism of collagen fibrillogenesis in fibrotic hearts of patients with advanced CKD have been largely unstudied.
METHODS
We analyzed explanted human left ventricular (LV) heart tissues in a three-arm cross-sectional cohort study of deceased donor patients on hemodialysis (HD, =18), hypertension with preserved renal function (HTN, =8), and healthy controls (CON, =17), . RNA-seq and protein analysis was performed on human donor hearts and cardiac fibroblasts treated with mineral stressors (high phosphate and high calcium). Further mechanistic studies were performed using primary cardiac fibroblasts, treated with mineral stressors, proinflammatory and profibrotic cytokines.
RESULTS
Of the 43 donor participants, there was no difference in age ( > 0.2), sex ( > 0.8), or body mass index ( > 0.1) between the groups. Hearts from the HD group had extensive fibrosis ( < 0.01). All LV tissues expressed only the trimeric form of collagen type I. HD hearts expressed increased collagen type I ( < 0.03), elevated collagen type I:III ratio ( < 0.05), and decreased MMP1 ( < 0.05) and MMP2 ( < 0.05). RNA-seq revealed no significant differential gene expression of extracellular matrix proteins of interest in HD hearts, but there was significant upregulation of LH2, periostin, -SMA, and TGF-1 gene expression in mineral stressor–treated cardiac fibroblasts. Both mineral stressors ( < 0.009) and cytokines ( < 0.03) increased collagen type I:III ratio. Mineral stressors induced trimeric collagen type I, but cytokine treatment induced only dimeric collagen type I in cardiac fibroblasts. Mineral stressors downregulated fibronectin ( < 0.03) and MMP2 zymogen ( < 0.01) but did not significantly affect expression of periostin, MMP1, or cross-linking enzymes. TGF- upregulated fibronectin ( < 0.01) and periostin ( < 0.02) only.
CONCLUSIONS
Myocardial fibrosis in advanced CKD hearts is characterized by increased trimeric collagen type I and dysregulated collagen metabolism, and is differentially regulated by components of uremia.
Topics: Humans; Myocardium; Heart Failure; Cardiomyopathies; Fibrosis; Renal Insufficiency, Chronic
PubMed: 37858297
DOI: 10.34067/KID.0000000000000276 -
JACC. Cardiovascular Imaging Aug 2023Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume...
BACKGROUND
Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume (ECV) mapping provides a surrogate measure of the myocardial, liver, and spleen amyloid burden.
OBJECTIVES
The purpose of this study was to assess multiorgan response to treatment using ECV mapping, and assess the association between multiorgan treatment response and prognosis.
METHODS
The authors identified 351 patients who underwent baseline serum amyloid-P-component (SAP) scintigraphy and cardiac magnetic resonance at diagnosis, of which 171 had follow-up imaging.
RESULTS
At diagnosis, ECV mapping demonstrated that 304 (87%) had cardiac involvement, 114 (33%) significant hepatic involvement, and 147 (42%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial HR: 1.03 [95% CI: 1.01-1.06]; P = 0.009; liver HR: 1.03; [95% CI: 1.01-1.05]; P = 0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R = 0.751; P < 0.001; R = 0.765; P < 0.001, respectively). Serial measurements demonstrated ECV correctly identified changes in liver and spleen amyloid load derived from SAP scintigraphy in 85% and 82% of cases, respectively. At 6 months, more patients with a good hematologic response had liver (30%) and spleen (36%) ECV regression than myocardial regression (5%). By 12 months, more patients with a good response demonstrated myocardial regression (heart 32%, liver 30%, spleen 36%). Myocardial regression was associated with reduced median N-terminal pro-brain natriuretic peptide (P < 0.001), and liver regression with reduced median alkaline phosphatase (P = 0.001). Changes in myocardial and liver ECV, 6 months after initiating chemotherapy, independently predict mortality (myocardial HR: 1.11 [95% CI: 1.02-1.20]; P = 0.011; liver HR: 1.07 [95% CI: 1.01-1.13]; P = 0.014).
CONCLUSIONS
Multiorgan ECV quantification accurately tracks treatment response and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. Baseline myocardial and liver ECV and changes at 6 months independently predict mortality, even after adjusting for traditional predictors of prognosis.
Topics: Humans; Contrast Media; Predictive Value of Tests; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Myocardium; Amyloid; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging, Cine
PubMed: 37178079
DOI: 10.1016/j.jcmg.2023.02.019 -
The British Journal of Radiology Oct 2023During the last 30 years, we have assisted to a great implementation in anticancer treatment with a subsequent increase of cancer survivors and decreased mortality. This... (Review)
Review
During the last 30 years, we have assisted to a great implementation in anticancer treatment with a subsequent increase of cancer survivors and decreased mortality. This has led to an ongoing interest about the possible therapy-related side-effects and their management to better guide patients therapy and surveillance in the chronic and long-term setting. As a consequence cardio-oncology was born, involving several different specialties, among which radiology plays a relevant role. Till the end of August 2022, when European Society of Cardiology (ESC) developed the first guidelines on cardio-oncology, no general indications existed to guide diagnosis and treatment of cancer therapy-related cardiovascular toxicity (CTR-CVT). They defined multimodality imaging role in primary and secondary prevention strategies, cancer treatment surveillance and early CTR-CVT identification and management. Cardiac computed tomography angiography (CCTA) has acquired a central role in coronary assessment, as far as coronary artery disease (CAD) exclusion is concerned; but on the side of this well-known application, it also started to be considered in left ventricular function evaluation, interstitial fibrosis quantification and cardiac perfusion studies. Cardiac magnetic resonance (CMR), instead, has been acknowledged as the gold standard alternative to trans-thoracic echocardiography (TTE) poor acoustic window in quantification of heart function and strain modifications, as well as pre- and post-contrast tissue characterization by means of T1-T2 mapping, early Gadolinium enhancement (EGE), late Gadolinium enhancement (LGE) and extracellular volume (ECV) evaluation. Our review is intended to provide a focus on the actual role of CMR and CCTA in the setting of a better understanding of cardiotoxicity and to draw some possible future directions of cardiac imaging in this field, starting from the recently published ESC guidelines.
Topics: Humans; Contrast Media; Computed Tomography Angiography; Gadolinium; Magnetic Resonance Imaging; Myocardium; Magnetic Resonance Spectroscopy; Neoplasms; Predictive Value of Tests; Magnetic Resonance Imaging, Cine; Ventricular Function, Left
PubMed: 37493228
DOI: 10.1259/bjr.20220999 -
Biomolecules Sep 2023Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease....
Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. To fill this gap, plasma sEVs were isolated from 42 STEMI patients treated by primary percutaneous coronary intervention (pPCI) and evaluated by CMR between days 3 and 6. Nanoparticle tracking analysis showed that sEVs were greater in patients with anterior STEMI ( = 0.0001), with the culprit lesion located in LAD ( = 0.045), and in those who underwent late revascularization ( = 0.038). A smaller sEV size was observed in patients with a low myocardial salvage index (MSI, = 0.014). Patients with microvascular obstruction (MVO) had smaller sEVs ( < 0.002) and lower expression of the platelet marker CD41-CD61 ( = 0.039). sEV size and CD41-CD61 expression were independent predictors of MVO/MSI (OR [95% CI]: 0.93 [0.87-0.98] and 0.04 [0-0.61], respectively). In conclusion, we provide evidence that the CD41-CD61 expression in sEVs reflects the CMR-assessed ischemic damage after STEMI. This finding paves the way for the development of a new strategy for the timely identification of high-risk patients and their treatment optimization.
Topics: Humans; ST Elevation Myocardial Infarction; Myocardium; Magnetic Resonance Imaging; Percutaneous Coronary Intervention; Inflammation
PubMed: 37892152
DOI: 10.3390/biom13101470