International Journal of Drug Discovery and Pharmacology

Modeling Arrhythmia in a Dish: An Open View from Human-Engineered Heart Constructs

2025-02-06T21:30:51+08:00

Review

Modeling Arrhythmia in a Dish: An Open View from Human-Engineered Heart Constructs

Shiya Wang^1,†, Pengcheng Yang^1,2,†, Jonathan Nimal Selvaraj^1,* and Donghui Zhang^1,3,*

¹ State Key Laboratory of Biocatalysts and Enzyme Engineering, Stem Cells and Tissue Engineering Manufacture Center, School of Life Sciences, Hubei University, Wuhan 430062, China

² Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Beijing100084, China

³ Cardiovascular Research Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

* Correspondence: jonathannimals@hubu.edu.cn (J.N.S.); dongh.zhang@hubu.edu.cn (D.Z.)

^† These authors contributed equally to this work.

Received: 26 July 2024; Revised: 29 September 2024; Accepted: 30 September 2024; Published: 6 February 2025

Abstract: Human-engineered heart constructs (hEHC), comprising cardiac organoids and engineered heart tissues, have become essential for replicating pathological and physiological mechanisms associated with cardiac development and diseases. The ongoing advancements in fabrication and culture techniques for these constructs have rendered them increasingly vital for cardiotoxicity prediction and drug efficacy evaluations. There is an escalating demand for standardized methodologies encompassing uniform fabrication, accurate disease modeling, and multidimensional phenotype assessments to facilitate a comprehensive understanding of these constructs. This review systematically examines hEHC, highlighting recent advancements in their cellular composition and functional characteristics, while stressing the necessity for thorough evaluations of significant heart disease phenotype, particularly in arrhythmia. Here, we propose a novel modular classification of cardiac model development based on specific modeling parameters and categorize existing research on in vitro functional assessment into various quantitative metrics. This classification framework provides researchers with innovative insights and strategies for personalized model design and evaluation.

Strategizing Cardiovascular Management in Diabetic Patients: Insights and Advancements from the 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients with Diabetes

2025-02-13T16:56:55+08:00

Communication

Strategizing Cardiovascular Management in Diabetic Patients: Insights and Advancements from the 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients with Diabetes

Hongyuan Zhang¹, Darren Green² and Yanrong Liu^1,3,*

¹ Michael Smith Building, Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M20 4BX, UK

² Vascular Research Group, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.

³ The Department of Cardiology, the 1st Affiliated Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China

* Correspondence: yanrong.liu@manchester.ac.uk

Received: 12 October 2023; Revised: 26 November 2023; Accepted: 27 November 2024; Published: 13 February 2025

Abstract: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The 2023 European Society of Cardiology (ESC) guidelines represent a significant advancement in the management of CVD in T2DM, building on the 2019 recommendations. Unlike previous iterations, the updated guidelines focus exclusively on T2DM, excluding pre-diabetes due to limited evidence directly linking it to cardiovascular risk. A notable addition is the SCORE2-Diabetes algorithm, which integrates diabetes-specific factors with traditional risk determinants to estimate the 10-year cardiovascular risk. This personalized risk stratification tool underscores the importance of early identification and management of key contributors, such as hyperglycemia and insulin resistance. The guidelines advocate for a multidisciplinary approach, emphasizing collaboration among diabetes, cardiovascular, and chronic kidney disease specialists to address the complex interplay of these conditions effectively. Moreover, the 2023 ESC guidelines highlight the necessity of individualized treatment strategies to reduce cardiovascular complications in T2DM. By reflecting the heterogeneity of diabetic populations and the evolving pharmacological landscape, these recommendations aim to optimize cardiovascular outcomes. This comprehensive update marks a critical step toward reducing the burden of CVD and improving the quality of life for patients with diabetes.

Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring

2025-02-13T16:56:52+08:00

Article

Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring

Wei Ge¹, Qiurong Wang^2,3, Jun Tao⁴, Stephen P. Ford^5,†, Wei Guo^6,7, Xiaoming Wang^8,* and Jun Ren^2,3,*

¹ Department of General Practice, Xijing Hospital, Air Force Medical University, Xi’an 710032, China

² Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China

³ National Clinical Research Center for Interventional Medicine, Shanghai 200032, China

⁴ Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China

⁵ Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY 82071, USA

⁶ Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA

⁷ Cardiovascular Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA

⁸ Department of Geriatrics, Xijing Hospital, Air Force Medical University, Xi’an 710032, China

* Correspondence: xmwang@fmmu.edu.cn (X.W.); ren.jun@zs-hospital.sh.cn (J.R.)

† Deceased.

Received: 19 October 2023; Revised: 23 November 2023; Accepted: 24 November 2024; Published: 13 February 2025

Abstract: The “thrifty phenotype” resulted from maternal malnutrition is considered a vital predisposing factor for the etiology of metabolic anomalies in offspring. To unveil the underlying mechanisms of heart diseases consequential to maternal malnutrition, pregnant ewes were kept on a nutrient restricted (NR: 50%) or control diet (100%) from day 28 to 78 of gestation. The experimental diet was then switched to a normal nutrition diet regimen till lambing. At 6 years of age, cardiac structure and function were evaluated following a 12-week palatable diet in adult offspring from control and maternal NR groups, along with insulin signaling, autophagy, mitophagy and pro-inflammatory cytokines. Our results revealed that offspring from NR ewes displayed greater body, heart, and ventricular weights along with cardiomyocyte mechanical anomalies (poor cell shortening capacity, prolonged relengthening and intracellular Ca²⁺ clearance with a pronounced response in left ventricles), cardiac remodeling (enlarged cardiomyocyte size and interstitial fibrosis) and O₂^- accumulation. Proinflammatory cytokines including TLR4, TNFα and IL1β were upregulated in right ventricles along with higher STAT3 in left ventricles with little changes in GLUT4 following maternal NR. Levels of autophagy and mitophagy were downregulated in both ventricles from NR offspring (LC3BII, Atg7, Parkin, FUNDC1 and BNIP3 with higher p62 and unchanged Beclin1). Maternal nutrient restriction also promoted serine phosphorylation of IRS1 and suppressed AMPK phosphorylation without affecting Akt phosphorylation in both ventricles. Phosphorylation of mTOR was elevated in left but not right ventricles from NR offspring. These findings collectively unveiled a predisposing role of maternal malnutrition in cardiac anomalies in adulthood, possibly related to regulation of phosphorylation of IRS1 and AMPK, proinflammatory cytokines, autophagy and mitophagy. Targeting autophagy/mitophagy, IRS1 and AMPK such as using metformin and HM-chromanone may hold therapeutic promises in NR offspring with cardiac conditions.

Coronary Microvascular Dysfunction: A Potential Intervention Strategy against Acute Myocardial Infarction

2025-02-14T15:38:47+08:00

Review

Coronary Microvascular Dysfunction: A Potential Intervention Strategy against Acute Myocardial Infarction

Zihan Wang 1, Lianhua Fang 1, Yang Lv 2, Shoubao Wang 1,*, and Guanhua Du 1,*

¹ Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

² Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

* Correspondence: shoubaowang@imm.ac.cn (S.W.); dugh@imm.ac.cn (G.D.)

Received: 26 August 2024; Revised: 11 October 2024; Accepted: 11 October 2024; Published: 14 February 2025

Abstract: Recent studies have illuminated the role of coronary microvascular dysfunction (CMD) as a pivotal contributor to acute myocardial infarction (AMI). Microvascular dysfunction may lead to severe results including microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH), which are associated with poor prognosis. This article reviews the current research on coronary microvascular dysfunction in myocardial infarction reperfusion including the mechanisms, methods and models assessing CMD. This review emphasizes the importance of CMD and proposes potential avenues for future research in this field. Interventions for CMD may pave the way for novel treatment strategies in the management of acute myocardial infarction (AMI).

Research and Prospects on the Evaluation of Drug Cocrystal Permeability

2025-02-25T17:02:28+08:00

Review

Research and Prospects on the Evaluation of Drug Cocrystal Permeability

Shuang Li¹, Meiru Liu¹, Dezhi Yang^1,*, Li Zhang^1,*, Yang Lu^1,* and Guanhua Du²

¹ Beijing City Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

²Beijing Key Laboratory of Drug Targets Identification and Drug Screening, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

* Correspondence: ydz@imm.ac.cn (D.Y.); zhangl@imm.ac.cn (L.Z.); luy@imm.ac.cn (Y.L.)

Received: 29 August 2024; Revised: 14 October 2024; Accepted: 15 October 2024; Published: 24 February 2025

Abstract: In developing new drugs, drug permeability assessment is crucial. Lead compounds exhibiting inadequate permeability often produce low bioavailability, rendering them inappropriate as drugs. The cocrystallization technique is a valuable tool for optimizing the physical and chemical properties of active pharmaceutical ingredients (APIs) and enhancing drug properties. This technique involves the introduction and weak interaction with cocrystal formers to produce supramolecular substances without altering the chemical structure of APIs, effectively improving their solubility and permeability and thereby significantly increasing their bioavailability. Consequently, drug cocrystal research has become a focal point for researchers in drug development. This study provides a comprehensive overview of four commonly employed methods for evaluating drug permeability and summarizes the applicability of each method to provide a reference for improving and refining the permeability evaluation method of drug cocrystals.

Ginsenoside Re Ameliorates Cardiac Hypertrophy by Regulating CaSR-Mediated Signaling Pathway

2025-03-05T12:54:54+08:00

Article

Ginsenoside Re Ameliorates Cardiac Hypertrophy by Regulating CaSR-Mediated Signaling Pathway

Panpan Chen^1,2,3, Mubo Liu^1,2,3,4, Hong Xiao^1,2,4, Ting Luo^1,2,4, Hong Ling^1,2,4, Xiaoyan Chen⁵, Zongli Li⁴, Shangfu Xu^1,2, Zheng Li^1,2,4 and Jiang Deng^1,2,4,*

¹ Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China

² Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563000, China.

³ The Affiliated Aerospace Hospital of Zunyi Medical University, Guizhou Aerospace Hospital, Zunyi 563000, China

⁴ Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563000, China

⁵ Department of Pathophysiology, Zunyi Medical University, Zunyi 563000, China

* Correspondence: dengjiang1225@sina.com; Tel.: +86-851-2864-3411; Fax: +86-851-2864-2406

Received: 31 August 2024; Revised: 17 September 2024; Accepted: 19 September 2024; Published: 5 March 2025

Abstract: Cardiac hypertrophy is a compensatory response to pathological stimuli. Recent studies have suggested that calcium-sensing receptor (CaSR) plays an important role in the development of cardiac hypertrophy. Ginsenoside Re (Re) is a monoconstituent of the ginseng plant. Many studies have shown that Re has various beneficial pharmacological effects on the cardiovascular system. It remains uncertain if Re have an anti-cardiac hypertrophic effect through the modulation of the CaSR-mediated signaling pathway. In this research, we employed a rat model of cardiac hypertrophy to investigate the relationship between Re and CaSR. Significant reductions in blood pressure, left ventricle hypertrophic indexes, cross-sectional area of cardiomyocytes, and levels of the β-myosin heavy chain and atrial natriuretic peptide were observed in spontaneously hypertensive rats (SHR) after Re administration. In addition, Re improved cardiac structure and function in SHR. Furthermore, Re inhibited CaSR, calcineurin (CaN), nuclear factor of activated T cells 3 (NFAT3), phosphorylated zinc finger transcription factor 4 (p-GATA4), protein kinase C-β (PKC-β), rapidly accelerated fibrosarcoma-1 (Raf-1), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2). It also increased the expression of p-NFAT3 and mitogen-activated protein kinase phosphatase-1 (MKP-1). These findings suggest that Re has beneficial effects on cardiac hypertrophy in SHR. The mechanisms underlying these effects are the regulation of the PKC-MAPK axis and the CaSR-mediated signaling pathway.