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Understanding and Targeting Heart Failure: From Biology to Therapeutics

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 27278

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Dr. Lei Ye

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Guest Editor

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore
Interests: heart disease; cardiovascular; diabetes; molecular and cellular therapeutics; stem cells
Special Issues, Collections and Topics in MDPI journals

Dr. Wuqiang Zhu

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Guest Editor

Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
Interests: cradiomyocyte; cell cycle; regeneration; cardiotoxicity; nanoparticle
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jun Pu

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Guest Editor

Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Interests: inflammation; ischemia; remodeling; heart failure

Special Issue Information

Dear Colleagues,

An estimated 64.3 million people are living with heart failure worldwide. In developed countries, the prevalence of known heart failure is generally estimated at 1% to 2% of the general adult population. Because of a growing and ageing population, the total number of heart failure patients still continues to rise. In recent years, the striking development of molecular and cellular biology, especially genetics, stem cell biology, and developmental biology are transforming the way we understand and treat heart failure.

In this Special Issue, we invite cardiologists, geneticists, and cell and developmental biologists to submit research on the triggers, phenomena, mechanisms, and treatment associated with heart failure. Topics include but are not limited to genetics, genome editing, stem cells, drug development, chemically modified RNA, and next-generation DNA and RNA sequencing. Our aim is for this Special Issue to provide new insights into the understanding of the factors driving heat failure, attesting new therapeutic interventions targeting failing heart, and promoting novel diagnostic and therapeutic strategies for the failing heart.

Dr. Lei Ye
Dr. Wuqiang Zhu
Prof. Dr. Jun Pu
Guest Editors

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Keywords

developmental biology
genetics
stem cells
heart failure
cell therapy

Published Papers (10 papers)

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Editorial

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3 pages, 183 KiB

Open AccessEditorial

Editorial: Special Issue—Understanding and Targeting Heart Failure: From Biology to Therapeutics

by Jun Pu, Wuqiang Zhu and Lei Ye

Biology 2023, 12(11), 1384; https://doi.org/10.3390/biology12111384 - 30 Oct 2023

Viewed by 990

Abstract

An estimated 64 [...] Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

Research

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25 pages, 3496 KiB

Open AccessArticle

Functional Cardiovascular Characterization of the Common Marmoset (Callithrix jacchus)

by Lina Klösener, Sabine Samolovac, Ina Barnekow, Jessica König, Amir Moussavi, Susann Boretius, Dieter Fuchs, Astrid Haegens, Rabea Hinkel and Matthias Mietsch

Biology 2023, 12(8), 1123; https://doi.org/10.3390/biology12081123 - 11 Aug 2023

Cited by 1 | Viewed by 1151

Abstract

Appropriate cardiovascular animal models are urgently needed to investigate genetic, molecular, and therapeutic approaches, yet the translation of results from the currently used species is difficult due to their genetic distance as well as their anatomical or physiological differences. Animal species that are closer to the human situation might help to bridge this translational gap. The common marmoset (Callithrix jacchus) is an interesting candidate to investigate certain heart diseases and cardiovascular comorbidities, yet a basic functional characterization of its hemodynamic system is still missing. Therefore, cardiac functional analyses were performed by utilizing the invasive intracardiac pressure–volume loops (PV loop) system in seven animals, magnetic resonance imaging (MRI) in six animals, and echocardiography in five young adult male common marmosets. For a direct comparison between the three methods, only data from animals for which all three datasets could be acquired were selected. All three modalities were suitable for characterizing cardiac function, though with some systemic variations. In addition, vena cava occlusions were performed to investigate the load-independent parameters collected with the PV loop system, which allowed for a deeper analysis of the cardiac function and for a more sensitive detection of the alterations in a disease state, such as heart failure or certain cardiovascular comorbidities. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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13 pages, 3220 KiB

Open AccessArticle

Uncovering the Gene Regulatory Network of Endothelial Cells in Mouse Duchenne Muscular Dystrophy: Insights from Single-Nuclei RNA Sequencing Analysis

by Yan Shen, Il-man Kim, Mark Hamrick and Yaoliang Tang

Biology 2023, 12(3), 422; https://doi.org/10.3390/biology12030422 - 10 Mar 2023

Cited by 2 | Viewed by 1907

Abstract

Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the dystrophin gene, which leads to heart and respiratory failure. Despite the critical impact of DMD on endothelial cells (ECs), there is limited understanding of its effect on the endothelial gene network. The aim of this study was to investigate the impact of DMD on the gene regulatory network of ECs. Methods and Results: To gain insights into the role of the dystrophin muscular dystrophy gene (DMD) in ECs from Duchenne muscular dystrophy; the study utilized single-nuclei RNA sequencing (snRNA-seq) to evaluate the transcriptomic profile of ECs from skeletal muscles in DMD mutant mice (DMD^mut) and wild-type control mice. The analysis showed that the DMD mutation resulted in the suppression of several genes, including SPTBN1 and the upregulation of multiple long noncoding RNAs (lncRNAs). GM48099, GM19951, and GM15564 were consistently upregulated in ECs and skeletal muscle cells from DMD^mut, indicating that these dysregulated lncRNAs are conserved across different cell types. Gene ontology (GO) enrichment analysis revealed that the DMD mutation activated the following four pathways in ECs: fibrillary collagen trimer, banded collagen fibril, complex of collagen trimers, and purine nucleotide metabolism. The study also found that the metabolic pathway activity of ECs was altered. Oxidative phosphorylation (OXPHOS), fatty acid degradation, glycolysis, and pyruvate metabolism were decreased while purine metabolism, pyrimidine metabolism, and one carbon pool by folate were increased. Moreover, the study investigated the impact of the DMD mutation on ECs from skeletal muscles and found a significant decrease in their overall number, but no change in their proliferation. Conclusions: Overall, this study provides new insights into the gene regulatory program in ECs in DMD and highlights the importance of further research in this area. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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13 pages, 2381 KiB

Open AccessArticle

Transcriptome Profile Reveals Differences between Remote and Ischemic Myocardium after Acute Myocardial Infarction in a Swine Model

by María Pulido, María Ángeles de Pedro, Verónica Álvarez, Ana María Marchena, Virginia Blanco-Blázquez, Claudia Báez-Díaz, Verónica Crisóstomo, Javier G. Casado, Francisco Miguel Sánchez-Margallo and Esther López

Biology 2023, 12(3), 340; https://doi.org/10.3390/biology12030340 - 21 Feb 2023

Cited by 1 | Viewed by 1607

Abstract

Acute myocardial infarction (AMI) is the consequence of an acute interruption of myocardial blood flow delimiting an area with ischemic necrosis. The loss of cardiomyocytes initiates cardiac remodeling in the myocardium, leading to molecular changes in an attempt to recover myocardial function. The purpose of this study was to unravel the differences in the molecular profile between ischemic and remote myocardium after AMI in an experimental model. To mimic human myocardial infarction, healthy pigs were subjected to occlusion of the mid-left anterior descending coronary artery, and myocardial tissue was collected from ischemic and remote zones for omics techniques. Comparative transcriptome analysis of both areas was accurately validated by proteomic analysis, resulting in mitochondrion-related biological processes being the most impaired mechanisms in the infarcted area. Moreover, Immune system process-related genes were up-regulated in the remote tissue, mainly due to the increase of neutrophil migration in this area. These results provide valuable information regarding differentially expressed genes and their biological functions between ischemic and remote myocardium after AMI, which could be useful for establishing therapeutic targets for the development of new treatments. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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12 pages, 7200 KiB

Open AccessArticle

Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats

by Peng Wang, Ying Li, Baihui Yan, Zhong Yang, Litao Li, Zhipeng Cao, Xuan Li, Ines Batinic-Haberle, Ivan Spasojevic, David S. Warner and Huaxin Sheng

Biology 2022, 11(7), 957; https://doi.org/10.3390/biology11070957 - 24 Jun 2022

Cited by 4 | Viewed by 1714

Abstract

Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP⁵⁺, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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13 pages, 2478 KiB

Open AccessArticle

Induction of Stem-Cell-Derived Cardiomyogenesis by Fibroblast Growth Factor 10 (FGF10) and Its Interplay with Cardiotrophin-1 (CT-1)

by Farhad Khosravi, Negah Ahmadvand, Maria Wartenberg and Heinrich Sauer

Biology 2022, 11(4), 534; https://doi.org/10.3390/biology11040534 - 30 Mar 2022

Cited by 5 | Viewed by 2065

Abstract

For heart regeneration purposes, embryonic stem cell (ES)-based strategies have been developed to induce the proliferation of cardiac progenitor cells towards cardiomyocytes. Fibroblast growth factor 10 (FGF10) contributes to cardiac development and induces cardiomyocyte differentiation in vitro. Yet, among pro-cardiogenic factors, including cardiotrophin-1 (CT-1), the hyperplastic function of FGF10 in cardiomyocyte turnover remains to be further characterized. We investigated the proliferative effects of FGF10 on ES-derived cardiac progenitor cells in the intermediate developmental stage and examined the putative interplay between FGF10 and CT-1 in cardiomyocyte proliferation. Mouse ES cells were treated with FGF10 and/or CT-1. Differential expression of cardiomyocyte-specific gene markers was analyzed at transcript and protein levels. Substantial upregulation of sarcomeric α-actinin was detected by qPCR, flow cytometry, Western blot and immunocytochemistry. FGF10 enhanced the expression of other structural proteins (MLC-2a, MLC-2v and TNNT2), transcriptional factors (NKX2-5 and GATA4), and proliferation markers (Aurora B and YAP-1). FGF10/CT-1 co-administration led to an upregulation of proliferation markers, suggesting the synergistic potential of FGF10 + CT-1 on cardiomyogenesis. In summary, we provided evidence that FGF10 and CT-1 induce cardiomyocyte structural proteins, associated transcription factors, and cardiac cell proliferation, which could be applicable in therapies to replenish damaged cardiomyocytes. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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Review

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13 pages, 1238 KiB

Open AccessReview

Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy

by Karim Ullah, Lizhuo Ai, Zainab Humayun and Rongxue Wu

Biology 2023, 12(7), 995; https://doi.org/10.3390/biology12070995 - 13 Jul 2023

Cited by 3 | Viewed by 1611

Abstract

Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα’s transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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17 pages, 1084 KiB

Open AccessReview

Nanoparticle Based Cardiac Specific Drug Delivery

by Dong Li, Yura Son, Michelle Jang, Shu Wang and Wuqiang Zhu

Biology 2023, 12(1), 82; https://doi.org/10.3390/biology12010082 - 04 Jan 2023

Cited by 3 | Viewed by 3381

Abstract

Heart failure secondary to myocardial injuries is a leading cause of death worldwide. Recently, a growing number of novel therapies have emerged for injured myocardium repairment. However, delivering therapeutic agents specifically to the injured heart remains a significant challenge. Nanoparticles are the most commonly used vehicles for targeted drug delivery. Various nanoparticles have been synthesized to deliver drugs and other therapeutic molecules to the injured heart via passive or active targeting approaches, and their targeting specificity and therapeutic efficacies have been investigated. Here, we summarized nanoparticle-based, cardiac-specific drug delivery systems, their potency for treating heart diseases, and the mechanisms underlying these cardiac-targeting strategies. We also discussed the clinical studies that have employed nanoparticle-based cardiac-specific drug delivery. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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36 pages, 7123 KiB

Open AccessReview

Cardiomyocyte Proliferation from Fetal- to Adult- and from Normal- to Hypertrophy and Failing Hearts

by Sanford P. Bishop, Jianyi Zhang and Lei Ye

Biology 2022, 11(6), 880; https://doi.org/10.3390/biology11060880 - 08 Jun 2022

Cited by 9 | Viewed by 2639

Abstract

The cardiomyocyte undergoes dramatic changes in structure, metabolism, and function from the early fetal stage of hyperplastic cell growth, through birth and the conversion to hypertrophic cell growth, continuing to the adult stage and responding to various forms of stress on the myocardium, often leading to myocardial failure. The fetal cell with incompletely formed sarcomeres and other cellular and extracellular components is actively undergoing mitosis, organelle dispersion, and formation of daughter cells. In the first few days of neonatal life, the heart is able to repair fully from injury, but not after conversion to hypertrophic growth. Structural and metabolic changes occur following conversion to hypertrophic growth which forms a barrier to further cardiomyocyte division, though interstitial components continue dividing to keep pace with cardiac growth. Both intra- and extracellular structural changes occur in the stressed myocardium which together with hemodynamic alterations lead to metabolic and functional alterations of myocardial failure. This review probes some of the questions regarding conditions that regulate normal and pathologic growth of the heart. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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15 pages, 1031 KiB

Open AccessReview

Cognitive Impairment in Heart Failure—A Review

by Fang Qin Goh, William K. F. Kong, Raymond C. C. Wong, Yao Feng Chong, Nicholas W. S. Chew, Tiong-Cheng Yeo, Vijay Kumar Sharma, Kian Keong Poh and Ching-Hui Sia

Biology 2022, 11(2), 179; https://doi.org/10.3390/biology11020179 - 23 Jan 2022

Cited by 15 | Viewed by 8272

Abstract

Cognitive impairment (CI) is common in heart failure (HF). Patients with HF demonstrate reduced global cognition as well as deficits in multiple cognitive domains compared to controls. Degree of CI may be related to HF severity. HF has also been associated with an increased risk of dementia. Anatomical brain changes have been observed in patients with HF, including grey matter atrophy and increased white matter lesions. Patients with HF and CI have poorer functional independence and self-care, more frequent rehospitalisations as well as increased mortality. Pathophysiological pathways linking HF and CI have been proposed, including cerebral hypoperfusion and impaired cerebrovascular autoregulation, systemic inflammation, proteotoxicity and thromboembolic disease. However, these mechanisms are poorly understood. We conducted a search on MEDLINE, Embase and Scopus for original research exploring the connection between HF and CI. We then reviewed the relevant literature and discuss the associations between HF and CI, the patterns of brain injury in HF and their potential mechanisms, as well as the recognition and management of CI in patients with HF. Full article

(This article belongs to the Special Issue Understanding and Targeting Heart Failure: From Biology to Therapeutics)

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