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Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease

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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 39429

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Dr. Cosmin Mihai Vesa

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Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
Interests: sustainability in public health; occupational medicine; environment-associated diseases; sick building syndrome; one health
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Simona Gabriela Bungau

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Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
Interests: medicine; pharmacology; antidiabetic drugs; metabolism; public health
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The purpose of this issue is to present the impact in clinical practice as well as in medical research of novel molecules that have been introduced in the treatment of diabetes mellitus, dyslipidemia, and cardiovascular disease. The topic focuses on the improvements in disease outcomes as well as the numerous beneficial effects of use of certain medications such as GLP-1 agonists, dual GLP-1/ GIP agonists, and SGLT-2 inhibitors for diabetes mellitus treatment; PCSK9 inhibitors and small interfering RNA (siRNA) molecules for dyslipidemia; and antiaggregants, oral anticoagulants, scubitril/valsartan, and non-steroidal mineralocorticoid receptor agonists or dapagliflozin in cardiovascular diseases. We believe that the number of real-life studies and in vivo and in vitro research of the effects of these drugs is quite low at the moment, leading to a lack of understanding of the complex molecular effects and pleiotropic effects of these medications, as well as incomplete knowledge regarding the repurposing of these drugs in clinical practice. Thus, this Special Issue is incredibly topical and important, and we look forward to your submissions which will help to clarify the issues surrounding such drugs.

Dr. Cosmin Mihai Vesa
Prof. Dr. Simona Gabriela Bungau
Guest Editors

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Keywords

GLP-1 agonists
GLP-1/GIP agonists
SGLT-2 inhibitors
dyslipidemia
PCSK9 inhibitors
diabetes mellitus
sacubitril/valsartan
small interfering RNA (siRNA) molecules for dyslipidemia
novel oral anticoagulants
non-steroidal MRA
cardiovascular disease

Published Papers (11 papers)

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Editorial

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2 pages, 183 KiB

Open AccessEditorial

Novel Molecules in Diabetes Mellitus, Dyslipidemia and Cardiovascular Disease

by Cosmin Mihai Vesa and Simona Gabriela Bungau

Int. J. Mol. Sci. 2023, 24(4), 4029; https://doi.org/10.3390/ijms24044029 - 17 Feb 2023

Cited by 22 | Viewed by 2354

Abstract

The purpose of this Special Issue is to present the impact in clinical practice as well as in medical research of novel molecules that have been introduced in the treatment of diabetes mellitus, dyslipidaemia, and cardiovascular disease [...] Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

Research

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12 pages, 1697 KiB

Open AccessArticle

Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes

by Éva Ruisanchez, Anna Janovicz, Rita Cecília Panta, Levente Kiss, Adrienn Párkányi, Zsuzsa Straky, Dávid Korda, Károly Liliom, Gábor Tigyi and Zoltán Benyó

Int. J. Mol. Sci. 2023, 24(9), 8375; https://doi.org/10.3390/ijms24098375 - 6 May 2023

Viewed by 1562

Abstract

Sphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measure changes in the tone of the thoracic aorta after administration of 0.2 U/mL neutral SMase in the presence or absence of the thromboxane prostanoid (TP) receptor antagonist SQ 29,548 and the nitric oxide synthase (NOS) inhibitor L-NAME. In precontracted aortic segments of non-diabetic mice, SMase induced transient contraction and subsequent weak relaxation, whereas vessels of diabetic (Lepr^db/Lepr^db, referred to as db/db) mice showed marked relaxation. In the presence of the TP receptor antagonist, SMase induced enhanced relaxation in both groups, which was 3-fold stronger in the vessels of db/db mice as compared to controls and could not be abolished by ceramidase or sphingosine-kinase inhibitors. Co-administration of the NOS inhibitor L-NAME abolished vasorelaxation in both groups. Our results indicate dual vasoactive effects of SMase: TP-mediated vasoconstriction and NO-mediated vasorelaxation. Surprisingly, in spite of the general endothelial dysfunction in T2DM, the endothelial NOS-mediated vasorelaxant effect of SMase was markedly enhanced. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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11 pages, 281 KiB

Open AccessArticle

Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes

by Zsolt Szekeres, Barbara Sandor, Zita Bognar, Fadi H. J. Ramadan, Anita Palfi, Beata Bodis, Kalman Toth and Eszter Szabados

Int. J. Mol. Sci. 2023, 24(5), 4405; https://doi.org/10.3390/ijms24054405 - 23 Feb 2023

Cited by 4 | Viewed by 2136

Abstract

Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

15 pages, 2016 KiB

Open AccessArticle

Pre-Diabetes-Linked miRNA miR-193b-3p Targets PPARGC1A, Disrupts Metabolic Gene Expression Profile and Increases Lipid Accumulation in Hepatocytes: Relevance for MAFLD

by Inês Guerra Mollet and Maria Paula Macedo

Int. J. Mol. Sci. 2023, 24(4), 3875; https://doi.org/10.3390/ijms24043875 - 15 Feb 2023

Cited by 2 | Viewed by 1840

Abstract

Distinct plasma microRNA profiles associate with different disease features and could be used to personalize diagnostics. Elevated plasma microRNA hsa-miR-193b-3p has been reported in patients with pre-diabetes where early asymptomatic liver dysmetabolism plays a crucial role. In this study, we propose the hypothesis that elevated plasma hsa-miR-193b-3p conditions hepatocyte metabolic functions contributing to fatty liver disease. We show that hsa-miR-193b-3p specifically targets the mRNA of its predicted target PPARGC1A/PGC1α and consistently reduces its expression in both normal and hyperglycemic conditions. PPARGC1A/PGC1α is a central co-activator of transcriptional cascades that regulate several interconnected pathways, including mitochondrial function together with glucose and lipid metabolism. Profiling gene expression of a metabolic panel in response to overexpression of microRNA hsa-miR-193b-3p revealed significant changes in the cellular metabolic gene expression profile, including lower expression of MTTP, MLXIPL/ChREBP, CD36, YWHAZ and GPT, and higher expression of LDLR, ACOX1, TRIB1 and PC. Overexpression of hsa-miR-193b-3p under hyperglycemia also resulted in excess accumulation of intracellular lipid droplets in HepG2 cells. This study supports further research into potential use of microRNA hsa-miR-193b-3p as a possible clinically relevant plasma biomarker for metabolic-associated fatty liver disease (MAFLD) in dysglycemic context. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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10 pages, 1696 KiB

Open AccessArticle

Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

by Deokho Lee, Yohei Tomita, Yukihiro Miwa, Heonuk Jeong, Ari Shinojima, Norimitsu Ban, Shintaro Yamaguchi, Ken Nishioka, Kazuno Negishi, Jun Yoshino and Toshihide Kurihara

Int. J. Mol. Sci. 2022, 23(23), 14711; https://doi.org/10.3390/ijms232314711 - 25 Nov 2022

Cited by 4 | Viewed by 2609

Abstract

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD⁺) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD⁺ levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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11 pages, 1109 KiB

Open AccessArticle

Synthesis of Glycolysis Inhibitor PFK15 and Its Synergistic Action with an Approved Multikinase Antiangiogenic Drug on Human Endothelial Cell Migration and Proliferation

by Jana Zlacká, Miroslav Murár, Gabriela Addová, Roman Moravčík, Andrej Boháč and Michal Zeman

Int. J. Mol. Sci. 2022, 23(22), 14295; https://doi.org/10.3390/ijms232214295 - 18 Nov 2022

Cited by 3 | Viewed by 1475

Abstract

Activated endothelial, immune, and cancer cells prefer glycolysis to obtain energy for their proliferation and migration. Therefore, the blocking of glycolysis can be a promising strategy against cancer and autoimmune disease progression. Inactivation of the glycolytic enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase) suppresses glycolysis level and contributes to decreased proliferation and migration of cancer (tumorigenesis) and endothelial (angiogenesis) cells. Recently, several glycolysis inhibitors have been developed, among them (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15) that is considered as one of the most promising. It is known that PFK15 decreases glucose uptake into the endothelial cells and efficiently blocks pathological angiogenesis. However, no study has described sufficiently PFK15 synthesis enabling its general availability. In this paper we provide all necessary details for PFK15 preparation and its advanced characterization. On the other hand, there are known tyrosine kinase inhibitors (e.g., sunitinib), that affect additional molecular targets and efficiently block angiogenesis. From a biological point of view, we have studied and proved the synergistic inhibitory effect by simultaneous administration of glycolysis inhibitor PFK15 and multikinase inhibitor sunitinib on the proliferation and migration of HUVEC. Our results suggest that suppressing the glycolytic activity of endothelial cells in combination with growth factor receptor blocking can be a promising antiangiogenic treatment. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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16 pages, 2131 KiB

Open AccessArticle

New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase

by Elena Tretyakova, Irina Smirnova, Oxana Kazakova, Ha Thi Thu Nguyen, Alina Shevchenko, Elena Sokolova, Denis Babkov and Alexander Spasov

Int. J. Mol. Sci. 2022, 23(21), 13535; https://doi.org/10.3390/ijms232113535 - 4 Nov 2022

Cited by 5 | Viewed by 1529

Abstract

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1–50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC₅₀ values of 35.57–65.98 μM, emerged as being good inhibitors of α-GLy. Arylidene 1β-hydroxy and 1β,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26–29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35–38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC₅₀ values of 0.15 to 0.68 μM, being 1206 to 266 more active than acarbose (IC₅₀ of 181.02 μM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with K_i of 50.45 μM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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9 pages, 2173 KiB

Open AccessArticle

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

by Deokho Lee, Yohei Tomita, Yukihiro Miwa, Ari Shinojima, Norimitsu Ban, Shintaro Yamaguchi, Ken Nishioka, Kazuno Negishi, Jun Yoshino and Toshihide Kurihara

Int. J. Mol. Sci. 2022, 23(19), 11228; https://doi.org/10.3390/ijms231911228 - 23 Sep 2022

Cited by 9 | Viewed by 3200

Abstract

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD⁺) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl₂-induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway (Nrf2 and Hmox-1) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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Review

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14 pages, 1373 KiB

Open AccessReview

Statins in Children, an Update

by Riccardo Fiorentino and Francesco Chiarelli

Int. J. Mol. Sci. 2023, 24(2), 1366; https://doi.org/10.3390/ijms24021366 - 10 Jan 2023

Cited by 7 | Viewed by 7162

Abstract

Since lipid abnormalities tend to progress from childhood to adulthood, it is necessary to early identify and treat children and adolescents with dyslipidemia. This is important in order to reduce the cardiovascular risk, delay the development of fatty streaks, slow the progression of atherosclerosis and reverse atherosclerotic plaques. Together with therapeutic lifestyle changes, statins are the most common lipid-lowering drugs. By inhibiting the endogenous cholesterol synthesis in the liver, statins increase the catabolism of LDL-C, reduce VLDL-C, IDL-C and TG and modestly increase HDL-C. Regardless of their lipid-lowering effect, statins have also pleiotropic effects. Statins have increasingly been prescribed in children and adolescents and mounting evidence suggests their beneficial role. As with adults, in children, several studies have demonstrated that statin therapy is efficient at lowering lipid levels and reducing CIMT progression and cumulative estimated atherosclerotic burden in children. Statins are generally very well-tolerated in both adults and children and adverse events are quite uncommon. When evaluating the need and the timing for statin treatment, the presence of several factors (secondary causes, familial history, additional risk factors) should also be considered. Before initiating statins, it is imperative for clinical practitioners to consult patients and families and, as with any new medication therapy, to monitor patients taking statins. Despite being safe and effective, many children with lipid disorders are not on statin therapy and are not receiving the full potential benefit of adequate lipid-lowering therapies. It is therefore important that clinicians become familiar with statins. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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16 pages, 907 KiB

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Tirzepatide: A Systematic Update

by Imma Forzano, Fahimeh Varzideh, Roberta Avvisato, Stanislovas S. Jankauskas, Pasquale Mone and Gaetano Santulli

Int. J. Mol. Sci. 2022, 23(23), 14631; https://doi.org/10.3390/ijms232314631 - 23 Nov 2022

Cited by 14 | Viewed by 10272

Abstract

Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1–5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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20 pages, 2031 KiB

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Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure

by Diana-Carina Iovanovici, Simona Gabriela Bungau, Cosmin Mihai Vesa, Madalina Moisi, Elena Emilia Babes, Delia Mirela Tit, Tunde Horvath, Tapan Behl and Marius Rus

Int. J. Mol. Sci. 2022, 23(19), 11336; https://doi.org/10.3390/ijms231911336 - 26 Sep 2022

Cited by 5 | Viewed by 3043

Abstract

Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment. Full article

(This article belongs to the Special Issue Novel Molecules in Diabetes Melitus, Dyslipidemia and Cardiovascular Disease)

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