implantation-left-ventricular-assist-device-lvad-juvenile-landrace

Implantation of Left Ventricular Assist Device (LVAD) in Juvenile Landrace Swine: A LVAD Implantation Model of Pediatric Heart Failure

A pediatric left ventricular assist device (LVAD) implantation model was established to simulate pediatric LVAD support and research the mechanism of ...

Chinese Academy of Medical Sciences and Peking Union Medical College

Targeted therapy refers to exploiting the specific therapeutic drugs against the pathogenic molecules (a protein or a gene) or cells. The drug specifically binds to disease-causing molecules or cells without affecting normal tissue, thus enabling personalized and precision treatment. Initially, therapeutic drugs included antibodies and small molecules, (e.g. nucleic acid drugs). With the advancement of the biology technology and immunotherapy, the gene editing and cell editing techniques are utilized for the disease treatment. Currently, targeted therapies applied to treat cardiovascular diseases (CVDs) mainly include protein drugs, gene editing technologies, nucleic acid drugs and cell therapy. Although targeted therapy has demonstrated excellent efficacy in pre-clinical and clinical trials, several limitations need to be recognized and overcome in clinical application, (e.g. off-target events, gene mutations, etc.). This review introduces the mechanisms of different targeted therapies, and mainly describes the targeted therapy applied in the CVDs. Furthermore, we made comparative analysis to clarify the advantages and disadvantages of different targeted therapies. This overview is expected to provide a new concept to the treatment of the CVDs.

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era.

Cardiac function is closely related to heart metabolism. Heart failure patients undergoing LVAD support have shown varying degrees of remodeling of both cardiac function and morphology. However, the metabolic changes in patients with different outcomes are unclear. This study aimed to identify metabolic differences and evaluate metabolomics-based biomarkers in patients with non-improved/improved cardiac function after LVAD support. Sixteen patients were enrolled in this study. Plasma samples were analyzed by using untargeted metabolomic approaches. Multivariate statistical analysis and a Mann-Whitney U-test was performed to clarify the separation in metabolites and to identify changes in plasma metabolites between the two groups, respectively. The efficacy of candidate biomarkers was tested by the area under the curve receiver operating characteristic curve. Using the Metabolomics Standards Initiative level 2, a total of 1542 and 619 metabolites were detected in the positive and negative ion modes, respectively. Enrichment analysis showed that metabolites in improved cardiac function patients were mainly involved in carbohydrate metabolism and amino acid metabolism. Metabolites from non-improved cardiac function patients were mainly involved in hormone metabolism. Furthermore, we found tris(hydroxymethyl)aminomethane and 5-guanidino-3-methyl-2-oxopentanoic acid could serve as biomarkers to predict whether a patient's cardiac function would improve after LVAD support.

Changes of Plasma Tris(hydroxymethyl)aminomethane and 5-Guanidino-3-methyl-2-oxopentanoic Acid as Biomarkers of Heart Remodeling after Left Ventricular Assist Device Support.

[This corrects the article DOI: 10.3389/fphar.2021.623674.].

Corrigendum: Targeted therapy in cardiovascular disease: A precision therapy era.

Macrophages play an essential role in the pathogenesis of autoimmune myocarditis, but the molecular mechanism remains largely unknown. Here, the role of Stimulator of interferon gene (Sting) in autoimmune myocarditis was investigated. Six-week-old male BALB/c mice received two subcutaneous injections of 250 μg α-MyHC peptide to establish experimental autoimmune myocarditis (EAM). With single-cell RNA sequencing analysis of cardiac immune (Cd45) cells, Sting was found to initiate proinflammatory macrophage differentiation related to the acute EAM phase. Furthermore, proinflammatory macrophages contribute to the pathogenesis of EAM via hypoxia-inducible factor-1α (Hif1α). A higher expression level of Sting was detected in macrophages from myocarditis, which was positively correlated with Hif1α expression. Single-stranded DNA (ssDNA) accumulation in macrophages in myocarditis was observed in the hearts of EAM mice. Pharmacological blockade of STING by C-176 (a specific inhibitor) ameliorated the inflammatory response of EAM and reduced proinflammatory molecule (Ifn-β, Tnf-α, Ccl2, and F4/80) expression and Hif1α expression. In vitro studies revealed that ssDNA activated the expression of Sting; in turn, Sting accelerated proinflammatory molecule expression in mouse macrophages. Inhibition of Hif1α expression could reduce Sting-associated cardiac inflammation and proinflammatory molecule expression. In addition, the expression of STING and ssDNA accumulation in macrophages were observed in human autoimmune myocarditis heart samples. STING activated proinflammatory macrophage via HIF1A, promoting the development of autoimmune myocarditis. The STING signaling pathway might provide a novel mechanism of autoimmune myocarditis and serve as a potential therapeutic target for autoimmune myocarditis patients.

STING regulates the transformation of the proinflammatory macrophage phenotype by HIF1A into autoimmune myocarditis.

The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could be better than IL2RA antagonists. By using single-cell RNA sequencing of immune cells at different time points in patients receiving IL2RA antagonists, we identified nineteen types of cells. We revealed higher IL2RA expression in regulatory T cells (Tregs), suggesting that IL2RA antagonists attenuated IL-2-induced Treg activation. CD4_C04_IFNGR1 and CD8_C05_IFITM2 which had more cytotoxic effects, remained elevated at later time points. IFNGR1 was upregulated in these two subtypes, but was not expressed in Treg. Ruxolitinib targeted the pathways of IFNGR1 (JAK1/2) while not affecting the pathway of IL-2-induced Tregs activation (JAK3). Ruxolitinib showed prolonged survival compared to IL2RA mAb-treated mice. Our study provided dynamic changes of immune cells after IL2RA antagonists treatment at single-cell resolution. Ruxolitinib has potential as a new immunoinduction therapy without affecting Treg.

Ruxolitinib attenuates acute rejection and can serve as an immune induction therapy in heart transplantation.

Aging is a global challenge, marked in the lungs by function decline and structural disorders, which affects the health of the elderly population. To explore anti-aging strategies, we develop a dynamic atlas covering 45 cell types in human lungs, spanning from embryonic development to aging. We aim to apply the discoveries of lung's development to address aging-related issues. We observe that both epithelial and immune cells undergo a process of acquisition and loss of essential function as they transition from development to aging. During aging, we identify cellular phenotypic alternations that result in reduced pulmonary compliance and compromised immune homeostasis. Furthermore, we find a distinctive expression pattern of the ferritin light chain (FTL) gene, which increases during development but decreases in various types of lung cells during the aging process.

A single-cell atlas of lung homeostasis reveals dynamic changes during development and aging.

This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by pathogenic mutations in the  () gene. The study included 170 patients who had a confirmed diagnosis of ARVC and underwent  genetic screening using next-generation sequencing. The findings of this study provide valuable insights into the association between  mutations and ARVC, which can aid in the development of more effective diagnostic and treatment strategies for ARVC patients. Out of the patients evaluated, six had a rare pathogenic mutation in  with the same p.R14del variant. Family screening revealed that heterozygous carriers of p.R14del exhibited a definite ARVC phenotype. In clinical studies, individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations. After adjusting for covariates, individuals with  mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess  mutations (95% CI 1.08-6.82,  = 0.035). The accumulation of left ventricular fat and fibers is a pathological marker for ARVC patients with p.R14del mutations. In a cohort of 170 Chinese ARVC patients, three point five percent of probands had the  pathogenic variant (p.R14del) and all were female. Our data shows that -related ARVC patients are at high risk for ventricular arrhythmias and heart failure, which requires clinical differentiation from classic ARVC. Furthermore, carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.

A Heterozygous  Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy.

The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR.

Overexpression of  in Cardiomyocytes Promotes Cardiac Reverse Remodeling.

Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM.

Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength.

Xenotransplantation offers a transformative solution to the global organ shortage crisis. However, the survival of xenografts remains limited despite various proposed strategies. In this study, we present an endothelial cell protection strategy that extends graft survival through the  construction of biomimetic glycan-enriched nanofibers. These biomimetic glycan-enriched molecules specifically target integrin αβ and form a polysaccharide-structured nanofiber network on the vascular endothelial surface. This network protects endothelial cells without compromising their normal physiological functions. The constructed biomimetic glycan-enriched layer significantly increased the xenograft survival by 1.64-fold compared to the untreated groups. This work introduces a novel strategy to enhance the survival of heart xenografts.

In Situ Biomimetic Glycocalyx Layer Protects Endothelial Damage in Xenotransplantation.

Fibro-fatty replacement of the myocardium plays a key role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and may be associated with progressive heart failure (HF). We aimed to investigate the characteristic of the fibro-fatty tissues of ACM patients and the plasma chemokines levels according to HF burden.

Plasma CCL3 predicts adverse heart failure outcomes in patients with arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by arrhythmias and an increased risk of sudden cardiac death, particularly in left-dominant arrhythmogenic cardiomyopathy (LACM), which primarily affects the left ventricle. This study aims to elucidate the cellular and molecular mechanisms underlying LACM by performing an in-depth single-nucleus RNA sequencing (snRNA-seq) analysis to identify key transcriptional signatures and pathways involved in the disease's pathogenesis.

Article	Year
Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era. Frontiers in pharmacology\| PubMed ID: 33935716	2021
Changes of Plasma Tris(hydroxymethyl)aminomethane and 5-Guanidino-3-methyl-2-oxopentanoic Acid as Biomarkers of Heart Remodeling after Left Ventricular Assist Device Support. Metabolites\| PubMed ID: 36355151	2022
Corrigendum: Targeted therapy in cardiovascular disease: A precision therapy era. Frontiers in pharmacology\| PubMed ID: 36817135	2023
STING regulates the transformation of the proinflammatory macrophage phenotype by HIF1A into autoimmune myocarditis. International immunopharmacology\| PubMed ID: 37354779	2023
Ruxolitinib attenuates acute rejection and can serve as an immune induction therapy in heart transplantation. Clinical immunology (Orlando, Fla.)\| PubMed ID: 38008145	2023
A single-cell atlas of lung homeostasis reveals dynamic changes during development and aging. Communications biology\| PubMed ID: 38589700	2024
A Heterozygous Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy. Phenomics (Cham, Switzerland)\| PubMed ID: 38605909	2024
Overexpression of in Cardiomyocytes Promotes Cardiac Reverse Remodeling. Circulation. Heart failure\| PubMed ID: 38910562	2024
Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength. Cardiovascular research\| PubMed ID: 39270732	2024
In Situ Biomimetic Glycocalyx Layer Protects Endothelial Damage in Xenotransplantation. Nano letters\| PubMed ID: 40062533	2025
Plasma CCL3 predicts adverse heart failure outcomes in patients with arrhythmogenic cardiomyopathy. BMC medicine\| PubMed ID: 40223064	2025
Molecular features and cell composition of left-dominant arrhythmogenic cardiomyopathy reveals key pathways and therapeutic targets. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology\| PubMed ID: 40383406	2025

Mengda Xu

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