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Metabolic Regulation in the Development of Cardiovascular Disease and Heart Failure

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 26190

Special Issue Editor


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Guest Editor
Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
Interests: cardiology; heart failure; cardiac arrest
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Metabolic regulation is strongly related to the development of cardiovascular disease and heart failure. Different metabolic diseases could predispose to the occurrence of systolic and diastolic dysfunction and, consequently, to heart failure. Among those, impaired glucose metabolism is the metabolic condition most commonly associated with a greater incidence of both coronary artery disease and heart failure. Novel classes of hypoglycemic drugs, such as type 2 sodium-glucose cotransporter inhibitors (SGLT2i) or GLP-1 agonists, are demonstrated to exert greater cardio- and nefro-protection. In particular, SGLT2i are able to reduce the risk of heart failure occurrence as well as of heart failure progression.  

However, metabolic regulation in cardiovascular disease and heart failure is complex, and the different stages are characterized by differences in metabolic and hormonal status. In patients with advanced heart failure, the dysregulation of metabolism is associated with a greater catabolic status due to a number of pathophysiological mechanisms, which are responsible for paradoxical epidemiology and cardiac cachexia. The study of the metabolic therapeutic approaches to treat heart failure patients at different stages is a challenging field of research. This Special Issue aims to present a collection of reviews and original papers that better clarify the pathophysiological, diagnostic, and therapeutic aspects of metabolic regulation related to the risk of cardiovascular disease occurrence through to the onset and progression of heart failure. 

Dr. Massimo Iacoviello
Guest Editor

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Keywords

  • diabetes
  • metabolism
  • dyslipidemia
  • cardiovascular disease
  • heart failure
  • diagnosis
  • prognosis
  • therapy

Published Papers (10 papers)

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Editorial

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4 pages, 186 KiB  
Editorial
Metabolic Regulation in the Development of Cardiovascular Disease and Heart Failure
by Massimo Iacoviello
Int. J. Mol. Sci. 2023, 24(10), 8773; https://doi.org/10.3390/ijms24108773 - 15 May 2023
Viewed by 718
Abstract
The Special Issue “Metabolic Regulation in the Development of Cardiovascular Disease and Heart Failure” focused on how metabolic diseases could cause a predisposition to cardiovascular diseases and, in particular, heart failure due to systolic or diastolic dysfunction or a combination thereof [...] Full article

Research

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13 pages, 1070 KiB  
Article
Circulating Levels of Ferritin, RDW, PTLs as Predictive Biomarkers of Postoperative Atrial Fibrillation Risk after Cardiac Surgery in Extracorporeal Circulation
by Claudia Altieri, Calogera Pisano, Labriola Vincenzo, Maria Sabrina Ferrante, Valentina Pellerito, Paolo Nardi, Carlo Bassano, Dario Buioni, Ernesto Greco, Giovanni Ruvolo and Carmela Rita Balistreri
Int. J. Mol. Sci. 2022, 23(23), 14800; https://doi.org/10.3390/ijms232314800 - 26 Nov 2022
Cited by 5 | Viewed by 1587
Abstract
Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery in conventional extracorporeal circulation (CECC), with an incidence of 15–50%. The POAF pathophysiology is not known, and no blood biomarkers exist. However, an association between increased ferritin levels and increased AF [...] Read more.
Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery in conventional extracorporeal circulation (CECC), with an incidence of 15–50%. The POAF pathophysiology is not known, and no blood biomarkers exist. However, an association between increased ferritin levels and increased AF risk, has been demonstrated. Based on such evidence, here, we evaluated the effectiveness of ferritin and other haematological parameters as POAF risk biomarkers in patients subjected to cardiac surgery. We enrolled 105 patients (mean age = 70.1 ± 7.1 years; 70 men and 35 females) with diverse heart pathologies and who were subjected to cardiothoracic surgery. Their blood samples were collected and used to determine hematological parameters. Electrocardiographic and echocardiographic parameters were also evaluated. The data obtained demonstrated significantly higher levels of serum ferritin, red cell distribution width (RDW), and platelets (PLTs) in POAF patients. However, the serum ferritin resulted to be the independent factor associated with the onset POAF risk. Thus, we detected the ferritin cut-off value, which, when ≥148.5 ng/mL, identifies the subjects at the highest POAF risk, and with abnormal ECG atrial parameters, such as PW indices, and altered structural heart disease variables. Serum ferritin, RDW, and PTLs represent predictive biomarkers of POAF after cardiothoracic surgery in CECC; particularly, serum ferritin combined with anormal PW indices and structural heart disease variables can represent an optimal tool for predicting not only POAF, but also the eventual stroke onset. Full article
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11 pages, 2097 KiB  
Article
Blood Reflux-Induced Epigenetic Factors HDACs and DNMTs Are Associated with the Development of Human Chronic Venous Disease
by Shun-Fu Chang, Hsiao-En Tsai, Jong-Tar Kuo, Yu-Rong Ruan, Chiu-Yen Chen, Shin-Yi Wang, Po-Yu Liu and Ding-Yu Lee
Int. J. Mol. Sci. 2022, 23(20), 12536; https://doi.org/10.3390/ijms232012536 - 19 Oct 2022
Cited by 4 | Viewed by 1170
Abstract
Blood reflux and metabolic regulation play important roles in chronic venous disease (CVD) development. Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) serve as repressors that inhibit metabolic signaling, which is induced by proatherogenic flow to promote aortic endothelial cell (EC) dysfunction and atherosclerosis. [...] Read more.
Blood reflux and metabolic regulation play important roles in chronic venous disease (CVD) development. Histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) serve as repressors that inhibit metabolic signaling, which is induced by proatherogenic flow to promote aortic endothelial cell (EC) dysfunction and atherosclerosis. The aim of this study was to elucidate the relationship between blood reflux and epigenetic factors HDACs and DNMTs in CVD. Human varicose veins with different levels of blood reflux versus normal veins with normal venous flow were examined. The results show that HDAC-1, -2, -3, -5, and -7 are overexpressed in the endothelium of varicose veins with blood reflux. Blood reflux-induced HDACs are enhanced in the varicose veins with a longer duration time of blood reflux. In contrast, these HDACs are rarely expressed in the endothelium of the normal vein with normal venous flow. Similar results are obtained for DNMT1 and DNMT3a. Our findings suggest that the epigenetic factors, HDACs and DNMTs, are induced in venous ECs in response to blood reflux but are inhibited in response to normal venous flow. Blood reflux-induced HDACs and DNMTs could inhibit metabolic regulation and promote venous EC dysfunction, which is highly correlated with CVD pathogenesis. Full article
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20 pages, 3079 KiB  
Article
Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4
by Bernd Stratmann, Britta Eggers, Yvonne Mattern, Tayana Silva de Carvalho, Katrin Marcus and Diethelm Tschoepe
Int. J. Mol. Sci. 2022, 23(13), 7255; https://doi.org/10.3390/ijms23137255 - 29 Jun 2022
Cited by 3 | Viewed by 1854
Abstract
An oversupply of nutrients with a loss of metabolic flexibility and subsequent cardiac dysfunction are hallmarks of diabetic cardiomyopathy. Even if excess substrate is offered, the heart suffers energy depletion as metabolic fluxes are diminished. To study the effects of a high glucose [...] Read more.
An oversupply of nutrients with a loss of metabolic flexibility and subsequent cardiac dysfunction are hallmarks of diabetic cardiomyopathy. Even if excess substrate is offered, the heart suffers energy depletion as metabolic fluxes are diminished. To study the effects of a high glucose supply, a stably glucose transporter type 4 (GLUT4)-overexpressing cell line presenting an onset of diabetic cardiomyopathy-like phenotype was established. Long-term hyperglycaemia effects were analysed. Rat cardiomyoblasts overexpressing GLUT4 (H9C2KE2) were cultured under normo- and hyperglycaemic conditions for long-term. Expression profiles of several proteins were compared to non-transfected H9C2 cells (H9C2) using RT-qPCR, proteomics-based analysis, or Western blotting. GLUT4 surface analysis, glucose uptake, and cell morphology changes as well as apoptosis/necrosis measurements were performed using flow cytometry. Additionally, brain natriuretic peptide (BNP) levels, reactive oxygen species (ROS) formation, glucose consumption, and lactate production were quantified. Long-term hyperglycaemia in H9C2KE2 cells induced increased GLUT4 presence on the cell surface and was associated with exaggerated glucose influx and lactate production. On the metabolic level, hyperglycaemia affected the tricarboxylic acid (TCA) cycle with accumulation of fumarate. This was associated with increased BNP-levels, oxidative stress, and lower antioxidant response, resulting in pronounced apoptosis and necrosis. Chronic glucose overload in cardiomyoblasts induced by GLUT4 overexpression and hyperglycaemia resulted in metabolically stimulated proteome profile changes and metabolic alterations on the TCA level. Full article
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18 pages, 736 KiB  
Article
PACAP-38 and PAC1 Receptor Alterations in Plasma and Cardiac Tissue Samples of Heart Failure Patients
by Dóra Szabó, Zsolt Sárszegi, Beáta Polgár, Éva Sághy, Dóra Reglődi, Tünde Tóth, Zsófia Onódi, Przemyslaw Leszek, Zoltán V. Varga, Zsuzsanna Helyes, Ágnes Kemény, Péter Ferdinandy and Andrea Tamás
Int. J. Mol. Sci. 2022, 23(7), 3715; https://doi.org/10.3390/ijms23073715 - 28 Mar 2022
Cited by 10 | Viewed by 2337
Abstract
Pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) is a multifunctional neuropeptide, which may play a role in cardioprotection. However, little is known about the presence of PACAP-38 in heart failure (HF) patients. The aim of our study was to measure the alterations of PACAP-38 [...] Read more.
Pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) is a multifunctional neuropeptide, which may play a role in cardioprotection. However, little is known about the presence of PACAP-38 in heart failure (HF) patients. The aim of our study was to measure the alterations of PACAP-38 like immunoreactivity (LI) in acute (n = 13) and chronic HF (n = 33) and to examine potential correlations between PACAP-38 and HF predictors (cytokines, NT-proBNP). Tissue PACAP-38 LI and PAC1 receptor levels were also investigated in heart tissue samples of patients with HF. Significantly higher plasma PACAP-38 LI was detected in patients with acute HF, while in chronic HF patients, a lower level of immunoreactivity was observed compared to healthy controls (n = 13). Strong negative correlation was identified between plasma PACAP-38 and NT-proBNP levels in chronic HF, as opposed to the positive connection seen in the acute HF group. Plasma IL-1 β, IL-2 and IL-4 levels were significantly lower in chronic HF, and IL-10 was significantly higher in patients with acute HF. PACAP-38 levels of myocardial tissues were lower in all end-stage HF patients and lower PAC1 receptor levels were detected in the primary dilated cardiomyopathy group compared to the controls. We conclude that PACAP-38 and PAC1 expression correlates with some biomarkers of acute and chronic HF; therefore, further studies are necessary to explore whether PACAP could be a suitable prognostic biomarker in HF patients. Full article
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Review

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16 pages, 753 KiB  
Review
Recent Pharmacological Options in Type 2 Diabetes and Synergic Mechanism in Cardiovascular Disease
by Aikaterini Andreadi, Saverio Muscoli, Rojin Tajmir, Marco Meloni, Carolina Muscoli, Sara Ilari, Vincenzo Mollace, David Della Morte, Alfonso Bellia, Nicola Di Daniele, Manfredi Tesauro and Davide Lauro
Int. J. Mol. Sci. 2023, 24(2), 1646; https://doi.org/10.3390/ijms24021646 - 13 Jan 2023
Cited by 19 | Viewed by 3584
Abstract
Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular [...] Read more.
Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes. Full article
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16 pages, 1948 KiB  
Review
Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients?
by Martina Belli, Lucy Barone, Alfonso Bellia, Domenico Sergi, Dalgisio Lecis, Francesca Romana Prandi, Marialucia Milite, Chiara Galluccio, Saverio Muscoli, Francesco Romeo and Francesco Barillà
Int. J. Mol. Sci. 2022, 23(23), 14598; https://doi.org/10.3390/ijms232314598 - 23 Nov 2022
Cited by 8 | Viewed by 4288
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, [...] Read more.
Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF. Full article
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13 pages, 1214 KiB  
Review
Involvement of circRNAs in the Development of Heart Failure
by Grażyna Sygitowicz and Dariusz Sitkiewicz
Int. J. Mol. Sci. 2022, 23(22), 14129; https://doi.org/10.3390/ijms232214129 - 16 Nov 2022
Cited by 12 | Viewed by 2053
Abstract
In recent years, interest in non-coding RNAs as important physiological regulators has grown significantly. Their participation in the pathophysiology of cardiovascular diseases is extremely important. Circular RNA (circRNA) has been shown to be important in the development of heart failure. CircRNA is a [...] Read more.
In recent years, interest in non-coding RNAs as important physiological regulators has grown significantly. Their participation in the pathophysiology of cardiovascular diseases is extremely important. Circular RNA (circRNA) has been shown to be important in the development of heart failure. CircRNA is a closed circular structure of non-coding RNA fragments. They are formed in the nucleus, from where they are transported to the cytoplasm in a still unclear mechanism. They are mainly located in the cytoplasm or contained in exosomes. CircRNA expression varies according to the type of tissue. In the brain, almost 12% of genes produce circRNA, while in the heart it is only 9%. Recent studies indicate a key role of circRNA in cardiomyocyte hypertrophy, fibrosis, autophagy and apoptosis. CircRNAs act mainly by interacting with miRNAs through a “sponge effect” mechanism. The involvement of circRNA in the development of heart failure leads to the suggestion that they may be promising biomarkers and useful targets in the treatment of cardiovascular diseases. In this review, we will provide a brief introduction to circRNA and up-to-date understanding of their role in the mechanisms leading to the development of heart failure. Full article
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13 pages, 2036 KiB  
Review
The Benefit of Sodium-Glucose Co-Transporter Inhibition in Heart Failure: The Role of the Kidney
by Edoardo Gronda, Emilio Vanoli, Massimo Iacoviello, Pasquale Caldarola, Domenico Gabrielli and Luigi Tavazzi
Int. J. Mol. Sci. 2022, 23(19), 11987; https://doi.org/10.3390/ijms231911987 - 9 Oct 2022
Cited by 7 | Viewed by 3128
Abstract
In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na+ and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na+ concentration in the filtrate by the [...] Read more.
In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na+ and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na+ concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O2 consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na+ coupled with glucose and can restore renal O2 demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes. Full article
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29 pages, 1544 KiB  
Review
Remodeling and Fibrosis of the Cardiac Muscle in the Course of Obesity—Pathogenesis and Involvement of the Extracellular Matrix
by Jagoda Kruszewska, Agnieszka Cudnoch-Jedrzejewska and Katarzyna Czarzasta
Int. J. Mol. Sci. 2022, 23(8), 4195; https://doi.org/10.3390/ijms23084195 - 11 Apr 2022
Cited by 31 | Viewed by 4357
Abstract
Obesity is a growing epidemiological problem, as two-thirds of the adult population are carrying excess weight. It is a risk factor for the development of cardiovascular diseases (hypertension, ischemic heart disease, myocardial infarct, and atrial fibrillation). It has also been shown that chronic [...] Read more.
Obesity is a growing epidemiological problem, as two-thirds of the adult population are carrying excess weight. It is a risk factor for the development of cardiovascular diseases (hypertension, ischemic heart disease, myocardial infarct, and atrial fibrillation). It has also been shown that chronic obesity in people may be a cause for the development of heart failure with preserved ejection fraction (HFpEF), whose components include cellular hypertrophy, left ventricular diastolic dysfunction, and increased extracellular collagen deposition. Several animal models with induced obesity, via the administration of a high-fat diet, also developed increased heart fibrosis as a result of extracellular collagen accumulation. Excessive collagen deposition in the extracellular matrix (ECM) in the course of obesity may increase the stiffness of the myocardium and thereby deteriorate the heart diastolic function and facilitate the occurrence of HFpEF. In this review, we include a rationale for that process, including a discussion about possible putative factors (such as increased renin–angiotensin–aldosterone activity, sympathetic overdrive, hemodynamic alterations, hypoadiponectinemia, hyperleptinemia, and concomitant heart diseases). To address the topic clearly, we include a description of the fundamentals of ECM turnover, as well as a summary of studies assessing collagen deposition in obese individuals. Full article
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