Special Issue "Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction"

A special issue of Hearts (ISSN 2673-3846).

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editors

Prof. Dr. I.Tong Mak
E-Mail Website
Guest Editor
Department of Biochemistry & Molecular Medicine, George Washington University, Washington, DC 20037, USA
Interests: cardiovascular injury and dysfunction; contribution of Mg deficiency; roles of anti-retroviral drugs and anti-cancer EGFR-TKIs; lysosomal iron and effects of beta-blockers; neurogenic inflammation; intervention by SP-receptor blockade; oxidative/nitrosative stress; glutathione status; genomic regulation of the Nrf2 pathway
Prof. Dr. Jay H. Kramer
E-Mail Website
Co-Guest Editor
Department of Biochemistry & Molecular Medicine, George Washington University, Washington, DC 20037, USA
Interests: free radicals [reactive oxygen/nitrogen species]; free radical spin trapping; antioxidants; adverse side effects of anti-cancer EGFR-tyrosine kinase inhibitors; lipid peroxidation; experimental cardiac ischemia-reperfusion injury and dysfunction; iron overload; magnesium deficiency; neurogenic inflammation and use of substance P receptor antagonists; experimental echocardiography

Special Issue Information

Cardiac injury manifested as either systolic or diastolic dysfunction is considered an important preceding stage leading to or associated with eventual heart failure. There is increasing literature recognizing that deficiency and/or imbalance of certain essential micronutrients, vitamins, and macrominerals may be involved in the pathogenesis of cardiomyopathy/injury/contractile dysfunction. Essential micronutrients may include, but not limited to, water soluble B vitamins such as thiamine, vitamin C, fat-soluble vitamins (A, E, D, K), carnitine, Coenzyme Q10, and taurine (a conditionally essential amino acid), as well as microminerals, such as selenium, zinc, copper, cobalt, and chromium. Notable macrominerals may include magnesium, calcium, iron, and potassium. While much of the nutritional deficiency might be caused by poor dietary intake, certain nutrient deficiencies, especially of Mg leading to hypomagnesemia, may be caused by excessive alcohol intake, antiretroviral drug treatments of HIV/AIDS patients, or anticancer therapeutics such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and cisplatin. Anticancer drugs may cause kidney injury and dysfunction, leading to malabsorption of Mg and renal Mg wasting. Many of the listed micronutrients are co-factors of metabolic reactions, and their deficiency would disturb myocardial substrate metabolism and energy utilization. Mg plays a key role in modulating neuronal excitation, endothelial function, and cardiac contraction by regulating several ion channels, including K and Ca; Mg is also a key co-factor for mitochondrial ATP production. As such, Mg deficiency may contribute to the pathogenesis of cardiac arrhythmias and dysfunction. Iron can be a pro-oxidant mineral, but iron is essential for the development of normal red blood cells and healthy immune function, and its deficiency is the most widespread nutritional deficiency in the world.

While it remains unclear if any chronic nutrient deficiency-induced cardiac injury/dysfunction is readily reversible, no consistent nutritional supplementation has been recommended as a rescue strategy against cardiac injury/dysfunction. It is noted that many of the micronutrients have antioxidant properties (e.g., vitamins E and C, selenium, and Coenzyme Q10). Mg is a natural calcium blocker, and its elevated intake above normal levels may also produce antioxidative, anti-inflammatory effects in vivo. The purpose of this Special Issue is to provide a platform for recent experimental or clinical research that may shed new light on nutrient/mineral deficiencies or adverse drug effects that may impair cardiac function directly or indirectly. Common mechanistic parameters may involve systemic oxidative/nitrosative stress, neurogenic inflammation, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, oxidative/antioxidant gene up-regulation, and/or compromised antioxidant defenses, which may serve as prognostic mediators/events linked to induced cardiac injury/dysfunction. The ultimate goal is to search for a better understanding of the complex interactions and molecular mechanisms contributing to cardiac injury/dysfunction and potential effective mitigating interventions.

Prof. Dr. I.Tong Mak
Prof. Dr. Jay H. Kramer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Hearts is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cardiac injury/contractile dysfunction
  • Micronutrient deficiency
  • Macromineral deficiency or imbalance
  • Impact by cardiovascular and/or anti-cancer drugs
  • Systemic inflammation
  • Oxidative/nitrosative stress
  • Antioxidant defenses
  • Supplement and/or pathway interventions

Published Papers (7 papers)

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Editorial

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Open AccessEditorial
Preface to Hearts Special Issue “Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction”
Hearts 2020, 1(3), 149-151; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts1030015 - 03 Nov 2020
Viewed by 572
Abstract
Cardiac injury manifested as either systolic or diastolic dysfunction is considered an important preceding stage that leads to or is associated with eventual heart failure (HF) [...] Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)

Research

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Open AccessFeature PaperArticle
Experimental Hypomagnesemia Induces Neurogenic Inflammation and Cardiac Dysfunction
Hearts 2020, 1(2), 99-116; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts1020011 - 05 Sep 2020
Viewed by 703
Abstract
Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, [...] Read more.
Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, cardiovascular, renal and other systems. In Mg-deficient rodents, early elevations in circulating levels of the neuropeptide, substance P (SP) may trigger subsequent deleterious inflammatory/oxidative/nitrosative stress events. Evidence also suggests that activity of neutral endopeptidase (NEP, neprilysin), the major SP-degrading enzyme, may be impaired during later stages of Mg deficiency, and this may sustain the neurogenic inflammatory response. In this article, experimental findings using substance P receptor blockade, NEP inhibition, and N-methyl-D-aspartate (NMDA) receptor blockade demonstrated the connection between hypomagnesemia, neurogenic inflammation, oxidative stress and enhanced cardiac dysfunction. Proof of concept concerning neurogenic inflammation is provided using an isolated perfused rat heart model exposed to acute reductions in perfusate magnesium concentrations. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
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Review

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Open AccessReview
Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors
Hearts 2021, 2(1), 45-60; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts2010005 - 15 Jan 2021
Viewed by 368
Abstract
Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates [...] Read more.
Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
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Open AccessReview
Vitamin A as a Transcriptional Regulator of Cardiovascular Disease
Hearts 2020, 1(2), 126-145; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts1020013 - 21 Sep 2020
Viewed by 618
Abstract
Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both [...] Read more.
Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
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Open AccessReview
Mechanisms Underlying Development of Taurine-Deficient Cardiomyopathy
Hearts 2020, 1(2), 86-98; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts1020010 - 14 Aug 2020
Viewed by 758
Abstract
Taurine is a ubiquitous β-amino acid that plays an essential role in ensuring normal mitochondrial and myocardial function. In the mitochondria, taurine reacts with a tRNA forming a 5-taurinomethyluridine conjugate that primarily regulates the biosynthesis of the mitochondria encoded protein, ND6, which serves [...] Read more.
Taurine is a ubiquitous β-amino acid that plays an essential role in ensuring normal mitochondrial and myocardial function. In the mitochondria, taurine reacts with a tRNA forming a 5-taurinomethyluridine conjugate that primarily regulates the biosynthesis of the mitochondria encoded protein, ND6, which serves as a subunit of complex I of the respiratory chain. Impaired formation of the taurine conjugate reduces activity of complex I and plays a central role in the pathophysiology of the mitochondrial disease MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The restoration of mitochondrial levels of the taurine conjugate enhances electron flux through the respiratory chain, thereby preventing at least some of the symptoms of MELAS. Taurine therapy also diminishes the severity of congestive heart failure, an observation that led to its approval for the treatment of congestive heart failure in Japan. The review article discusses the role of defective calcium handling, reduced ATP generation, enhanced oxidative stress and apoptosis in the development of taurine-deficient cardiomyopathy. Some patients suffering from congestive heart failure are taurine-deficient, an observation supporting the hypothesis that low taurine levels contribute to the severity of heart failure. Thus, mishandling of taurine leads to mitochondrial dysfunction, which is involved in the development of both MELAS and congestive heart failure. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
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Other

Open AccessViewpoint
Extracellular and Intracellular Magnesium Deficiency Found in Pregnant Women with Preeclampsia and Gestational Diabetes Is Associated with Overexpression of Notch Proteins, Cytokines, p53, NF-kB and Proto-Oncogenes: Potential Importance in Growth Retardation, Stillbirths, Fetal Mutations and Increased Cardiovascular Risks and Stroke with Advancing Age in Pregnant Women
Hearts 2021, 2(1), 139-148; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts2010011 - 05 Mar 2021
Viewed by 360
Abstract
In 1983, three of us reported in “Science” that umbilical-placental arteries and veins, obtained from normal pregnant women at term delivery, when exposed in vitro to low concentrations of Mg2+ went into vasospasm; the lower the Mg2+, the greater the [...] Read more.
In 1983, three of us reported in “Science” that umbilical-placental arteries and veins, obtained from normal pregnant women at term delivery, when exposed in vitro to low concentrations of Mg2+ went into vasospasm; the lower the Mg2+, the greater the contractile force developed. These blood vessels also demonstrated amplified contractile force development when challenged with circulating amines and peptides (e.g., norepinephrine, 5-HT, angiotensin II, etc.). We suggested that severe Mg deficiency during pregnancy could in part be responsible for spontaneous abortions, loss of fetuses, stillbirths, and developmental alterations in infants. Using short-term dietary Mg deficient animals, we have noted a great many molecular and biochemical alterations in ventricular, atrial and somatic vascular smooth muscle alterations including DNA methylation and histone changes leading us to speculate that Mg deficiency may represent a genotoxin promoting mutations and causing epigenetic changes. Over the last 35 years, we have new data on severely preeclamptic and gestational diabetic pregnant women that gives credence to our original hypothesis and demonstrates that recently- discovered developmental proteins, originally found 100 years ago in Drosophila fruit flies termed the “Notch pathway”, due to effects on its wings, appears to be important in development of the umbilical-placental blood vessels in pregnant women. Along with the developmental molecule, p53, these Notch proteins clearly alter the behavior of the umbilical-placental vessels. We believe these new findings probably help to explain many of the genetic-toxicity effects seen in women later in life who develop strokes and cardiovascular diseases. Notch alterations could also play an important role in babies born with cardiac defects. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
Open AccessBrief Report
Deficiency in gp91Phox (NOX2) Protects against Oxidative Stress and Cardiac Dysfunction in Iron Overloaded Mice
Hearts 2020, 1(2), 117-125; https://0-doi-org.brum.beds.ac.uk/10.3390/hearts1020012 - 15 Sep 2020
Viewed by 564
Abstract
The role of NADPH oxidase subunit, gp91phox (NOX2) in development of oxidative stress and cardiac dysfunction due to iron (Fe)-overload was assessed. Control (C57BL/6J) and gp91phox knockout (KO) mice were treated for up to 8 weeks with Fe (2.5 mg/g/wk, i.p.) [...] Read more.
The role of NADPH oxidase subunit, gp91phox (NOX2) in development of oxidative stress and cardiac dysfunction due to iron (Fe)-overload was assessed. Control (C57BL/6J) and gp91phox knockout (KO) mice were treated for up to 8 weeks with Fe (2.5 mg/g/wk, i.p.) or Na-dextran; echocardiography, plasma 8-isoprostane (lipid peroxidation marker), cardiac Fe accumulation (Perl’s staining), and CD11b+ (WBCs) infiltrates were assessed. Fe caused no adverse effects on cardiac function at 3 weeks. At 6 weeks, significant declines in left ventricular (LV) ejection fraction (14.6% lower), and fractional shortening (19.6% lower) occurred in the Fe-treated control, but not in KO. Prolonging Fe treatment (8 weeks) maintained the depressed LV systolic function with a trend towards diastolic dysfunction (15.2% lower mitral valve E/A ratio) in controls but produced no impact on the KO. Fe-treatment (8 weeks) caused comparable cardiac Fe accumulation in both strains, but a 3.3-fold elevated plasma 8-isoprostane, and heightened CD11b+ staining in controls. In KO mice, lipid peroxidation and CD11b+ infiltration were 50% and 68% lower, respectively. Thus, gp91phox KO mice were significantly protected against oxidative stress, and systolic and diastolic dysfunction, supporting an important role of NOX2-mediated oxidative stress in causing cardiac dysfunction during Fe overload. Full article
(This article belongs to the Special Issue Nutrient Deficiency and Drug Induced Cardiac Injury and Dysfunction)
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