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29 pages, 4479 KiB

Open AccessArticle

Sexually Dimorphic Effects of CYP2B6 in the Development of Fasting-Mediated Steatosis in Mice: Role of the Oxylipin Products 9-HODE and 9-HOTrE

by Jazmine A. Eccles-Miller, Tyler D. Johnson and William S. Baldwin

Biomedicines 2025, 13(2), 295; https://doi.org/10.3390/biomedicines13020295 - 25 Jan 2025

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Abstract

Background: Cytochrome P450 2B6 (CYP2B6) is a sexually dimorphic, anti-obesity CYP enzyme responsible for the metabolism of xeno- and endobiotics, including the metabolism of polyunsaturated fatty acids (PUFAs) into 9-hydroxyoctadecadienoic acid (9-HODE) and 9-hydroxyoctadecatrienoic acid (9-HOTrE). However, humanized CYP2B6 transgenic (hCYP2B6-Tg) mice [...] Read more.

Background: Cytochrome P450 2B6 (CYP2B6) is a sexually dimorphic, anti-obesity CYP enzyme responsible for the metabolism of xeno- and endobiotics, including the metabolism of polyunsaturated fatty acids (PUFAs) into 9-hydroxyoctadecadienoic acid (9-HODE) and 9-hydroxyoctadecatrienoic acid (9-HOTrE). However, humanized CYP2B6 transgenic (hCYP2B6-Tg) mice are sensitive to diet-induced hepatic steatosis despite their resistance to obesity. The purpose of this study was to determine if 9-HODE, 9-HOTrE, or other factors contribute to the sexually dimorphic steatosis observed in hCYP2B6-Tg mice. Results: Cyp2b9/10/13-null (Cyp2b-null) mice were injected with either 9-HODE or 9-HOTrE for 2 days and were then subjected to a fasting period of 20 h to induce steatosis. Serum lipids were moderately increased, especially in females, after 9-HODE (triglycerides (TGs), very low-density lipoproteins (VLDLs)) and 9-HOTrE (high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), cholesterol) treatment. No change in hepatic lipids and few changes in hepatic gene expression were observed in mice treated with either oxylipin, suggesting that these oxylipins had minimal to moderate effects. Therefore, to further investigate CYP2B6’s role in steatosis, hCYP2B6-Tg and Cyp2b-null mice were subjected to a 20 h fast and compared. Both male and female hCYP2B6-Tg mice exhibited increased steatosis compared to Cyp2b-null mice. Serum cholesterol, triglycerides, HDLs, and VLDLs were increased in hCYP2B6-Tg males. Serum triglycerides and VLDLs were decreased in hCYP2B6-Tg females, suggesting the greater hepatic retention of lipids in females. Hepatic oxylipin profiles revealed eight perturbed oxylipins in female hCYP2B6-Tg mice and only one in males when compared to Cyp2b-null mice. RNA-seq also demonstrated greater effects in females in terms of the number of genes and gene ontology (GO) terms perturbed. There were only a few overlapping GO terms between sexes, and lipid metabolic processes were enriched in hCYP2B6-Tg male mice but were repressed in hCYP2B6-Tg females compared to Cyp2b-nulls. Conclusions: hCYP2B6-Tg mice are sensitive to fasting-mediated steatosis in males and females, although the responses are different. In addition, the oxylipins 9-HODE and 9-HOTrE are unlikely to be the primary cause of CYP2B6’s pro-steatotic effects. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

10 pages, 2468 KiB

Open AccessArticle

Analysis of Cardiovascular High-Risk Profile in Middle-Aged Lithuanian Men with Arterial Hypertension from 2009 to 2019

by Vaida Šileikienė, Vilma Dženkevičiūtė, Alma Čypienė, Tautvydas Šlapikas, Roma Puronaitė, Jolita Badarienė, Aleksandras Laucevičius, Eglė Butkevičiūtė and Egidija Rinkūnienė

Biomedicines 2025, 13(2), 272; https://doi.org/10.3390/biomedicines13020272 - 23 Jan 2025

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Abstract

Objective: The prevalence of arterial hypertension in adult men is 34% worldwide and 52% in Lithuania. This paper aims to provide an overview of the prevalence trends of arterial hypertension and its clinical forms in middle-aged Lithuanian men and to assess the [...] Read more.

Objective: The prevalence of arterial hypertension in adult men is 34% worldwide and 52% in Lithuania. This paper aims to provide an overview of the prevalence trends of arterial hypertension and its clinical forms in middle-aged Lithuanian men and to assess the risk profiles of the different groups. Methods: This retrospective research study collected data from 52,012 Lithuanian male patients. The study population consisted of men aged 40–55 who participated in the Lithuanian High Cardiovascular Risk Program between 2009 and 2019. Results: Of the 52,012 participants, 47.2% (n = 24,531) were men with arterial hypertension. The prevalence of arterial hypertension in Lithuanian men decreased between 2009 and 2019 (p < 0.001). Before the study visit, 12.6% (n = 6583) of men were unaware of their diagnosis, and 8.8% (n = 4555) of diagnosed cases were untreated. In addition, 2.6% (n = 1334) of the men had resistant arterial hypertension. Significant differences in most general characteristics were found between the groups with arterial hypertension. Waist circumference increased from 92.8 ± 10.7 cm in men without arterial hypertension to 109 ± 13.3 cm and in men with resistant arterial hypertension (p < 0.001), and mean triglyceride levels increased from 1.55 ± 1.22 mmol/L to 2.32 ± 1.82 mmol/L in these groups (p < 0.001). Obesity (63.6%), unhealthy diet (74.7%), physical inactivity (62.9%), and diabetes (25.2%) were more common in the group with resistant arterial hypertension than in all other groups (p < 0.001). Meanwhile, dyslipidaemia was the most common risk factor in all groups (from 83.2% in men without arterial hypertension to 92.6% in men with resistant hypertension). Conclusions: Almost half of middle-aged men had arterial hypertension, with prevalence decreasing from 2009 to 2019. Significant changes in cardiometabolic characteristics were observed in newly diagnosed cases of arterial hypertension. These changes are even more notable in men with resistant hypertension compared to a non-resistant form. Most cardiovascular risk factors were most prevalent in over 50% of resistant hypertension cases, with dyslipidaemia being the most common risk factor in the entire male sample. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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21 pages, 1869 KiB

Open AccessArticle

Beneficial Effect of Fenofibrate in Combination with Silymarin on Parameters of Hereditary Hypertriglyceridemia-Induced Disorders in an Animal Model of Metabolic Syndrome

by Jan Soukop, Ludmila Kazdová, Martina Hüttl, Hana Malínská, Irena Marková, Olena Oliyarnyk, Denisa Miklánková, Soňa Gurská, Zuzana Rácová, Martin Poruba and Rostislav Večeřa

Biomedicines 2025, 13(1), 212; https://doi.org/10.3390/biomedicines13010212 - 16 Jan 2025

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Abstract

Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for [...] Read more.

Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (−77%) and free fatty acids (−29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (−35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (−34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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16 pages, 903 KiB

Open AccessArticle

Role of Advanced Glycation End Products in Mediating Glycated Haemoglobin and Pulse Wave Velocity in Healthy Adults

by Irene Martínez-García, Alicia Saz-Lara, Carlos Pascual-Morena, Ana Díez-Fernández, Sara Valladolid-Ayllón, Bruno Bizzozero-Peroni, Óscar Martínez-Cifuentes, Eva Rodríguez-Gutiérrez and Iván Cavero-Redondo

Biomedicines 2025, 13(1), 137; https://doi.org/10.3390/biomedicines13010137 - 8 Jan 2025

Viewed by 690

Abstract

Background/Objectives: Poor metabolic control is associated with increased levels of advanced glycation end products (AGEs), which in turn may lead to increased arterial stiffness. The aim of this study was to estimate the association between glycated haemoglobin A1c (HbA1c) and aortic pulse [...] Read more.

Background/Objectives: Poor metabolic control is associated with increased levels of advanced glycation end products (AGEs), which in turn may lead to increased arterial stiffness. The aim of this study was to estimate the association between glycated haemoglobin A1c (HbA1c) and aortic pulse wave velocity (a-PWV) in healthy subjects and to analyse the mediating effect of AGEs measured by skin autofluorescence (SAF) on this association. Methods: HbA1c, a-PWV and SAF were analysed in 390 healthy Spanish subjects from the EVasCu study (42.02 ± 13.14 years, 63.08% females). A directed acyclic graph (DAG) was generated to define the covariates to be included, and the model was confirmed via multiple linear regression analysis. Descriptive and exploratory analyses were performed to investigate the associations between variables. Finally, adjusted and unadjusted mediation analyses were performed to verify the influence of SAF on the main association between HbA1c and a-PWV. Results: Multiple linear regression analyses for a-PWV supported the validity of the structure in the DAG. Descriptive and exploratory analyses revealed that when the models were adjusted to include all covariates, the statistical significance of the main association disappeared. Mediation analysis revealed that SAF mediated 35.77% of the effect of HbA1c on a-PWV in the unadjusted model and 42.18% after adjusting for covariates. Conclusions: Our study suggests that increases in HbA1c levels are associated with increases in a-PWV and that this relationship is mediated by the SAF score in healthy adults. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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12 pages, 679 KiB

Open AccessArticle

Effects of Continuous Positive Airway Pressure Treatment on Vascular Function in a Real-Life Cohort of Elderly Patients with Obstructive Sleep Apnoea Syndrome

by Mara Volpentesta, Valentino Condoleo, Alberto Panza, Giandomenico Severini, Luca Soraci, Cataldo Rotondo, Giuseppe Armentaro, Corrado Pelaia, Vanessa Teresa Fiorentino, Francesco Andreozzi, Giorgio Sesti, Andrea Corsonello and Angela Sciacqua

Biomedicines 2024, 12(11), 2563; https://doi.org/10.3390/biomedicines12112563 - 8 Nov 2024

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Abstract

Background: Obstructive sleep apnoea syndrome (OSAS) is an independent risk factor for cardiovascular morbidity and mortality and has a detrimental effect on vascular function, in particular on arterial stiffness and endothelial function. Continuous positive airway pressure (CPAP) is the gold-standard therapy for OSAS [...] Read more.

Background: Obstructive sleep apnoea syndrome (OSAS) is an independent risk factor for cardiovascular morbidity and mortality and has a detrimental effect on vascular function, in particular on arterial stiffness and endothelial function. Continuous positive airway pressure (CPAP) is the gold-standard therapy for OSAS and its effects on arterial stiffness and endothelial function have been demonstrated in non-elderly patients. Objectives: The objective of this study was to evaluate the effect of one year of CPAP treatment on arterial stiffness, through assessment of carotid–femoral pulse wave velocity (cf-PWV), and on endothelial function, through the reactive hyperaemia index (RHi), in a real-life cohort of elderly patients with moderate-to-severe OSAS and several comorbidities. Methods: In this nonrandomised prospective study, we enrolled 469 consecutive elderly patients affected by moderate-to-severe OSAS distributed in two groups: CPAP-treated (n = 225) and untreated patients (n = 244). Results: At one-year follow-up, in the treated group emerged an important improvement in poligraphics (AHI, ODI, TC90, mean SpO₂%), laboratory (HOMA index, eGFR, hs-CRP) and vascular function parameters: cf-PWV. The stepwise multivariate linear regression demonstrated a significant correlation between the delta of the polygraph parameters and the delta of PWV and RHi. Conclusions: Our study confirmed the favourable effects of CPAP therapy in a cohort of elderly patients affected by OSAS and several comorbidities on sleep respiratory parameters and vascular function; early diagnosis and treatment with CPAP might be beneficial to delay or prevent the occurrence of cardiovascular events in these groups of patients. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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24 pages, 6573 KiB

Open AccessArticle

Cellular Characteristics and Protein Signatures of Human Adipose Tissues from Donors With or Without Advanced Coronary Artery Disease

by Caitlin P. S. Ellis, Benjamin W. Tero, Christian M. Potts, Kimberly T. Malka, Xuehui Yang, Joshua Hamilton, Calvin Vary, Andre Khalil and Lucy Liaw

Biomedicines 2024, 12(11), 2453; https://doi.org/10.3390/biomedicines12112453 - 25 Oct 2024

Viewed by 891

Abstract

Background/Objectives: Perivascular adipose tissue (PVAT) exerts a paracrine effect on blood vessels and our objective was to understand PVAT molecular signatures related to cardiovascular disease. Methods: We studied two groups: those undergoing mitral valve repair/replacement (VR, n = 16) and coronary [...] Read more.

Background/Objectives: Perivascular adipose tissue (PVAT) exerts a paracrine effect on blood vessels and our objective was to understand PVAT molecular signatures related to cardiovascular disease. Methods: We studied two groups: those undergoing mitral valve repair/replacement (VR, n = 16) and coronary artery bypass graft (CABG, n = 38). VR donors did not have coronary artery disease, whereas CABG donors had advanced coronary artery disease. Clinical and tissue pathologies and proteomics from adipose tissue were assessed. Results: Donors undergoing VR had a lower body mass index (p = 0.01), HbA1C (p = 0.0023), and incidence of diabetes (p = 0.022) compared to CABG. VR donors were overall healthier, with higher cardiac function compared to CABG donors, based on ejection fraction. Although adipose histopathology between groups was not markedly different, PVAT had smaller and more adipocytes compared to subcutaneous adipose tissues. These differences were validated by whole specimen automated morphological analysis, and anisotropy analysis showed small (2.8–7.5 μm) and large (22.8–64.4 μm) scale differences between perivascular and subcutaneous adipose tissue from CABG donors, and small scale changes (2.8–7.5 μm) between perivascular and subcutaneous adipose tissue from VR donors. Distinct protein signatures in PVAT and subcutaneous adipose tissue include those involved in secretion, exosomes and vesicles, insulin resistance, and adipocyte identity. Comparing PVAT and subcutaneous adipose tissue from CABG donors, there were 82 significantly different proteins identified with log fold change ≥ 0.3 or ≤−0.3 (p < 0.05). Using this threshold, there were 36 differences when comparing PVAT and subcutaneous adipose tissue from VR donors, 58 differences when comparing PVAT from CABG or VR donors, and 55 when comparing subcutaneous adipose tissue from CABG vs. VR donors. Conclusions: Routine histopathology cannot differentiate between PVAT from donors with or without coronary artery disease, but multiscale anisotropy analysis discriminated between these populations. Our mass spectrometry analysis identified a cohort of proteins that distinguish between adipose depots, and are also associated with the presence or absence of coronary artery disease. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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12 pages, 2685 KiB

Open AccessArticle

Mitochondrial Dysfunction and Ion Imbalance in a Rat Model of Hemodialysis-Induced Myocardial Stunning

by Yuxin Nie, Liyu Lin, Qiang Yang, Jiachang Hu, Minmin Sun, Fangfang Xiang, Xuesen Cao, Jinbo Yu, Yaqiong Wang, Jie Teng, Xiaoqiang Ding, Bo Shen and Zhen Zhang

Biomedicines 2024, 12(10), 2402; https://doi.org/10.3390/biomedicines12102402 - 20 Oct 2024

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Abstract

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K⁺) and calcium (Ca²⁺) [...] Read more.

Background/Objectives: Hemodialysis-induced myocardial stunning (HIMS) is a frequent complication in patients undergoing maintenance hemodialysis, characterized by transient left ventricular dysfunction due to ischemic episodes. Mitochondrial dysfunction and fluctuations in key ions such as potassium (K⁺) and calcium (Ca²⁺) are implicated in the pathogenesis of HIMS. This study aims to investigate the role of mitochondrial dysfunction and the protective potential of mitochondrial ATP-sensitive potassium channels (mitoK_ATP) in mitigating HIMS. Methods: A 5/6 nephrectomy rat model was established to mimic chronic kidney disease and the subsequent HIMS. The effects of mitoK_ATP channel modulators were evaluated by administering diazoxide (DZX), a mitoK_ATP opener, and 5-hydroxydecanoate (5-HD), a mitoK_ATP blocker, before hemodialysis. Mitochondrial function was assessed by measuring membrane potential, ATP synthase activity, and intramitochondrial Ca²⁺ levels. Myocardial function was evaluated using speckle tracking echocardiography. Results: Rats undergoing hemodialysis exhibited significant reductions in left ventricular strain and synchrony. DZX administration significantly improved mitochondrial function and reduced myocardial strain compared to controls. Conversely, 5-HD worsened mitochondrial swelling and disrupted myocardial function. Higher K⁺ and Ca²⁺ concentrations in the dialysate were associated with improved mitochondrial energy metabolism and myocardial strain. Conclusions: Mitochondrial dysfunction and ion imbalances during hemodialysis are key contributors to HIMS. The activation of mitoK_ATP channels provides mitochondrial protection and may serve as a potential therapeutic strategy to mitigate HIMS. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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15 pages, 2326 KiB

Open AccessArticle

The Silent Threat: A Retrospective Cohort Study on the Impact of Prediabetes on ST-Elevation Myocardial Infarction Survival—A Call to Action!

by Elke Boxhammer, Matthias Hammerer, Christiana Schernthaner, Erika Prinz, Mathias C. Brandt, Michael Lichtenauer, Alexander E. Berezin, Wilfried Wintersteller, Uta C. Hoppe and Kristen L. Kopp

Biomedicines 2024, 12(10), 2223; https://doi.org/10.3390/biomedicines12102223 - 29 Sep 2024

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Abstract

Background: Prediabetes is frequently underdiagnosed and undertreated, yet it poses significant cardiovascular risks. This study investigates the impact of prediabetes on short- and long-term survival outcomes in patients who experienced ST-elevation myocardial infarction (STEMI). Methods: In this retrospective, single-center cohort study, we evaluated [...] Read more.

Background: Prediabetes is frequently underdiagnosed and undertreated, yet it poses significant cardiovascular risks. This study investigates the impact of prediabetes on short- and long-term survival outcomes in patients who experienced ST-elevation myocardial infarction (STEMI). Methods: In this retrospective, single-center cohort study, we evaluated 725 STEMI patients stratified into non-diabetic, prediabetic, and diabetic groups based on HbA1c levels at presentation. A Kaplan–Meier survival analysis was employed to compare long-term outcomes over a three-year follow-up period. Cardiovascular risk factors, including hypertension and dyslipidemia, were analyzed across the groups. The discriminatory power of HbA1c for predicting all-cause mortality was assessed using an Area Under the Receiver Operating Characteristic (AUROC) analysis. Results: Of the 725 patients, 407 (56.1%) were non-diabetic, 184 (25.4%) were prediabetic, and 134 (18.5%) were diabetic. Prediabetic patients exhibited significant additional cardiovascular risk factors, such as arterial hypertension (67.4%) and dyslipidemia (78.3%), with prevalence rates between those of non-diabetic and diabetic patients. The Kaplan–Meier analysis revealed that at a three-year follow-up, prediabetic patients faced a survival disadvantage, with a significant decrease in survival rates compared to non-diabetic patients (log-rank p = 0.016); their survival outcomes approached those of diabetic patients (p = 0.125). The AUROC analysis demonstrated that HbA1c was a significant predictor of short- and long-term mortality, with a cut-off value of 5.75% and an Area Under the Curve (AUC) of 0.580–0.617 (95% CI: 0.458–0.721), indicating a moderate ability to predict survival in patients with STEMI. Conclusions: Prediabetes significantly worsens survival outcomes following STEMI, nearly approaching the risk level of diabetes. Integrating rigorous cardiovascular risk management strategies for prediabetic individuals, including lifestyle interventions and potentially pharmacological treatments, could prevent the progression to diabetes and mitigate associated cardiovascular risks. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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10 pages, 702 KiB

Open AccessArticle

Assessing Cardiovascular Risk with Coronary Artery Calcium and Carotid Intima-Media Thickness in Patients with Negative Stress Echocardiography

by Narae Kim, Hui-Jeong Hwang and In-Ho Yang

Biomedicines 2024, 12(9), 2151; https://doi.org/10.3390/biomedicines12092151 - 23 Sep 2024

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Abstract

Background: The role of treadmill stress echocardiography (TSE) in symptomatic patients may be limited. We evaluated whether carotid intima-media thickness (cIMT) and coronary artery calcium (CAC) scores can predict cardiovascular (CV) outcomes in patients with negative TSE. Methods: Patients who had [...] Read more.

Background: The role of treadmill stress echocardiography (TSE) in symptomatic patients may be limited. We evaluated whether carotid intima-media thickness (cIMT) and coronary artery calcium (CAC) scores can predict cardiovascular (CV) outcomes in patients with negative TSE. Methods: Patients who had negative TSE and measured cIMT or CAC scoring were enrolled and followed up. The primary CV outcome was defined as a composite of acute coronary syndrome, coronary revascularization, heart failure, stroke, and CV death. Results: Overall, 1095 patients participated. The median follow-up duration was 5.8 years. Patients with increased cIMT and CAC scores experienced a high incidence of primary CV outcomes (normal vs. increased group on cIMT and CAC scoring: 4.4% vs. 20.0% and 0.4% vs. 25.0%, respectively, p < 0.001). In the Cox proportional hazard model, increased cIMT and CAC scores were associated with increased primary CV outcomes (adjusted hazard ratio [95% confidence interval], p-value for increased cIMT and increased CAC scores = 2.939 [1.241–6.960], p = 0.014 and 45.192 [5.497–371.505], p < 0.001, respectively). Conclusions: Patients with increased cIMT and CAC scores have poor CV outcomes even though they have negative TSE results, and therefore, they should be carefully monitored. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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11 pages, 1173 KiB

Open AccessArticle

miRNA in the Diagnosis and Treatment of Critical Limb Ischemia

by Alexandra Ioana Popescu, Andreea Luciana Rață, Daliborca Vlad, Cristian Vlad, Roxana Popescu, Ramona Roxana Onofrei, Marialuisa Morelli, Stelian Pantea and Sorin Barac

Biomedicines 2024, 12(9), 2026; https://doi.org/10.3390/biomedicines12092026 - 4 Sep 2024

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Abstract

Chronic threatening limb ischemia of the inferior limbs (CLTI) is the final stage of peripheral arterial disease (PAD) and is one of the most feared atherosclerotic manifestations because if left untreated, in time, it can lead to amputation. Although there are currently numerous [...] Read more.

Chronic threatening limb ischemia of the inferior limbs (CLTI) is the final stage of peripheral arterial disease (PAD) and is one of the most feared atherosclerotic manifestations because if left untreated, in time, it can lead to amputation. Although there are currently numerous treatment techniques, both open and endovascular, it is a pathology that has no underlying treatment. Therefore, current studies are very much focused on new therapeutic possibilities that can be applied in the early stages of the atherosclerotic process. In numerous studies in the literature, miRNAs have been identified as important markers of atherosclerosis. The present study aims to identify the expression of three miRNAs—miR-199a, miR-20a, and miR-30c—in patients with chronic limb-threatening ischemia in the pre- and post-revascularization periods. The aim of the study is to identify whether these three markers play a role in critical ischemia and whether they have the potential for future use in new treatments of this pathology. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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12 pages, 1708 KiB

Open AccessArticle

High Glucose Increases Lactate and Induces the Transforming Growth Factor Beta-Smad 1/5 Atherogenic Pathway in Primary Human Macrophages

by Kareem Awad, Laura Kakkola and Ilkka Julkunen

Biomedicines 2024, 12(7), 1575; https://doi.org/10.3390/biomedicines12071575 - 16 Jul 2024

Cited by 1 | Viewed by 1561

Abstract

Hundreds of millions of people worldwide are expected to suffer from diabetes mellitus. Diabetes is characterized as a dynamic and heterogeneous disease that requires deeper understanding of the pathophysiology, genetics, and metabolic shaping of this disease and its macro/microvascular complications. Macrophages play an [...] Read more.

Hundreds of millions of people worldwide are expected to suffer from diabetes mellitus. Diabetes is characterized as a dynamic and heterogeneous disease that requires deeper understanding of the pathophysiology, genetics, and metabolic shaping of this disease and its macro/microvascular complications. Macrophages play an essential role in regulating local immune responses, tissue homeostasis, and disease pathogenesis. Here, we have analyzed transforming growth factor beta 1 (TGFβ1)/Smad signaling in primary human macrophages grown in normal (NG) and high-glucose (HG; +25 mM glucose) conditions. Cell culture lactate concentration and cellular phosphofructokinase (PFK) activity were increased in HG concentrations. High glucose levels in the growth media led to increased macrophage mRNA expression of TGFβ1, and TGFβ-regulated HAMP and PLAUR mRNA levels, while the expression of TGFβ receptor II remained unchanged. Stimulation of cells with TGFβ1 protein lead to Smad2 phosphorylation in both NG and HG conditions, while the phosphorylation of Smad1/5 was detected only in response to TGFβ1 stimulation in HG conditions. The use of the specific Alk1/2 inhibitor dorsomorphin and the Alk5 inhibitor SB431542, respectively, revealed that HG conditions led TGFβ1 to activation of Smad1/5 signaling and its downstream target genes. Thus, high-glucose activates TGFβ1 signaling to the Smad1/5 pathway in primary human macrophages, which may contribute to cellular homeostasis in a harmful manner, priming the tissues for diabetic complications. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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23 pages, 2541 KiB

Open AccessArticle

Ketosis Suppression and Ageing (KetoSAge) Part 2: The Effect of Suppressing Ketosis on Biomarkers Associated with Ageing, HOMA-IR, Leptin, Osteocalcin, and GLP-1, in Healthy Females

by Isabella D. Cooper, Yvoni Kyriakidou, Lucy Petagine, Kurtis Edwards, Adrian Soto-Mota, Kenneth Brookler and Bradley T. Elliott

Biomedicines 2024, 12(7), 1553; https://doi.org/10.3390/biomedicines12071553 - 12 Jul 2024

Cited by 1 | Viewed by 4746

Abstract

Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer’s disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in [...] Read more.

Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer’s disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m² ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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28 pages, 44122 KiB

Open AccessArticle

External Support of Autologous Internal Jugular Vein Grafts with FRAME Mesh in a Porcine Carotid Artery Model

by Jaroslav Chlupac, Jan Frank, David Sedmera, Ondrej Fabian, Zuzana Simunkova, Iveta Mrazova, Tomas Novak, Zdenka Vanourková, Oldrich Benada, Zdenek Pulda, Theodor Adla, Martin Kveton, Alena Lodererova, Ludek Voska, Jan Pirk and Jiri Fronek

Biomedicines 2024, 12(6), 1335; https://doi.org/10.3390/biomedicines12061335 - 16 Jun 2024

Viewed by 1400

Abstract

Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in [...] Read more.

Background: Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in a preclinical model. Methods: We performed autologous internal jugular vein interposition grafting in porcine carotid arteries for one month. Four grafts were supported with a FRAME mesh, while seven unsupported grafts served as controls. The conduits were examined through flowmetry, angiography, macroscopy, and microscopy. Results: The one-month patency rate of FRAME-supported grafts was 100% (4/4), whereas that of unsupported controls was 43% (3/7, Log-rank p = 0.071). On explant angiography, FRAME grafts exhibited significantly more areas with no or mild stenosis (9/12) compared to control grafts (3/21, p = 0.0009). Blood flow at explantation was higher in the FRAME grafts (145 ± 51 mL/min) than in the controls (46 ± 85 mL/min, p = 0.066). Area and thickness of neo-intimal hyperplasia (NIH) at proximal anastomoses were similar for the FRAME and the control groups: 5.79 ± 1.38 versus 6.94 ± 1.10 mm², respectively (p = 0.558) and 480 ± 95 vs. 587 ± 52 μm²/μm, respectively (p = 0.401). However, in the midgraft portions, the NIH area and thickness were significantly lower in the FRAME group than in the control group: 3.73 ± 0.64 vs. 6.27 ± 0.64 mm², respectively (p = 0.022) and 258 ± 49 vs. 518 ± 36 μm²/μm, respectively (p = 0.0002). Conclusions: In our porcine model, the external mesh FRAME improved the patency of vein-to-carotid artery grafts and protected them from stenosis, particularly in the mid regions. The midgraft neo-intimal hyperplasia was two-fold thinner in the meshed grafts than in the controls. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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14 pages, 2873 KiB

Open AccessArticle

Importance of T1-Mapping Sequence in Patients with Hypertrophic Cardiomyopathy without Foci of Non-Ischemic Myocardial Injury in Late Gadolinium Enhancement Sequence

by Natalia Zdebik, Rafał Poręba and Paweł Gać

Biomedicines 2024, 12(6), 1330; https://doi.org/10.3390/biomedicines12061330 - 14 Jun 2024

Cited by 1 | Viewed by 1477

Abstract

Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients [...] Read more.

Background: The aim of this study was to assess the importance of T1-mapping sequences in the diagnosis of hypertrophic cardiomyopathy (HCM) in patients without foci of non-ischemic myocardial injury in classic cardiac magnetic resonance (CMR) sequences. Methods: Two groups were compared: 28 patients with HCM, without any foci of myocardial injury in the late gadolinium enhancement (LGE) sequence (HCM group), and 28 patients without cardiomyopathy (CON group). Classic CMR sequences and T1-mapping sequences were performed. The following parameters were assessed: T1 time of the whole left ventricular myocardium, T1 time of myocardium in the basal, middle and apical layers of the left ventricle, and T1 time in individual segments of the left ventricular myocardium. Myocardial extracellular volume (ECV) was assessed similarly. Results: ECV was significantly higher in the HCM group than in the CON group, for the whole left ventricular myocardium, for the basal and apical layers of the left ventricle, and for segments 1–3, 8, and 13–16 of the left ventricle. Regression analysis showed that a higher left-ventricular mass index (LVMI), a higher body mass index and older age are factors independently associated with a higher ECV of the whole myocardium but only in the group with LVMI ≥ 131.84 g/m². Conclusion: In patients with HCM without foci of non-ischemic myocardial injury, higher ECV values of the left ventricular myocardium are observed. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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18 pages, 2663 KiB

Open AccessArticle

Does Metabolic Syndrome and Its Components Have Prognostic Significance for Renal and Cardiovascular Outcomes in IgA Nephropathy?

by Balázs Sági, Tibor Vas, Botond Csiky, Judit Nagy and Tibor József Kovács

Biomedicines 2024, 12(6), 1250; https://doi.org/10.3390/biomedicines12061250 - 4 Jun 2024

Cited by 2 | Viewed by 1572

Abstract

Background: Patients with IgA nephropathy (IgAN), a chronic kidney disease (CKD), are significantly more likely to have cardiovascular (CV) mortality and morbidity than the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease [...] Read more.

Background: Patients with IgA nephropathy (IgAN), a chronic kidney disease (CKD), are significantly more likely to have cardiovascular (CV) mortality and morbidity than the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The purpose of this study was to determine how metabolic characteristics in a homogeneous population of CKD patients relate to prognosis. Methods: A total of 145 patients with CKD stages 1–4 diagnosed with IgA nephropathy (92 men and 53 women, aged 54.7 ± 13 years) were examined and monitored for a median of 190 months. All-cause mortality and any CV event, such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal), have been included in the composite endpoints (CV and renal). Results: Patients with MetS had significantly more primary endpoint events (23/65 patients vs. 15/60 patients, p < 0.001) compared to the non-MetS group. The MetS group had a statistically significant increase in both primary renal and CV endpoints (18/65 vs. 10/60, p = 0.001), and in CV endpoint events (7/65 vs. 6/60, p = 0.029) among the secondary endpoints (CV and renal separately). Based on Cox regression analysis, the main endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus. Independent predictors of secondary renal endpoints were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. When Kaplan–Meier curves were analyzed at the combined endpoints (CV and renal) or each endpoint independently, significant differences were seen between MetS and non-MetS. With more MetS components, the primary endpoint rate increased significantly (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). Conclusions: Our results show that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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11 pages, 4641 KiB

Open AccessArticle

Continuous Monitoring of Advanced Hemodynamic Parameters during Hemodialysis Demonstrated Early Variations in Patients Experiencing Intradialytic Hypotension

by Yotam Kolben, Ittamar Gork, David Peled, Shani Amitay, Peleg Moshel, Nir Goldstein, Arik Ben Ishay, Meir Fons, Michael Tabi, Arik Eisenkraft, Yftach Gepner and Dean Nachman

Biomedicines 2024, 12(6), 1177; https://doi.org/10.3390/biomedicines12061177 - 25 May 2024

Viewed by 2121

Abstract

Intradialytic hypotension (IDH) is a severe complication of hemodialysis (HD) with a significant impact on morbidity and mortality. In this study, we used a wearable device for the continuous monitoring of hemodynamic vitals to detect hemodynamic changes during HD and attempted to identify [...] Read more.

Intradialytic hypotension (IDH) is a severe complication of hemodialysis (HD) with a significant impact on morbidity and mortality. In this study, we used a wearable device for the continuous monitoring of hemodynamic vitals to detect hemodynamic changes during HD and attempted to identify IDH. End-stage kidney disease patients were continuously monitored 15 min before starting the session and until 15 min after completion of the session, measuring heart rate (HR), noninvasive cuffless systolic and diastolic blood pressure (SBP and DBP), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR). Data were analyzed retrospectively and included comparing BP measured by the wearable devices (recorded continuously every 5 s) and the cuff-based devices. A total of 98 dialysis sessions were included in the final analysis, and IDH was identified in 22 sessions (22.5%). Both SBP and DBP were highly correlated (r > 0.62, p < 0.001 for all) between the wearable device and the cuff-based measurements. Based on the continuous monitoring, patients with IDH had earlier and more profound reductions in SBP and DBP during the HD treatment. In addition, nearly all of the advanced vitals differed between groups. Further studies should be conducted in order to fully understand the potential of noninvasive advanced continuous monitoring in the prediction and prevention of IDH events. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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14 pages, 849 KiB

Open AccessArticle

The Randomized, Multicenter, Open-Label, Controlled POLBOS 3 Trial Comparing Regular Drug-Eluting Stents and the Sirolimus-Eluting BiOSS LIM C Dedicated Coronary Bifurcation Stent: Four-Year Results

by Robert J. Gil, Adam Kern, Krystian Bojko, Aneta Gziut-Rudkowska, Dobrin Vassilev and Jacek Bil

Biomedicines 2024, 12(5), 938; https://doi.org/10.3390/biomedicines12050938 - 23 Apr 2024

Viewed by 1162

Abstract

This multicenter, randomized study aimed to compare the sirolimus-eluting BiOSS LIM C dedicated coronary bifurcation stent with second-generation -limus drug-eluting stents (rDESs) in the treatment of non-left main (non-LM) coronary bifurcation. The deployment of a single stent in the main vessel–main branch across [...] Read more.

This multicenter, randomized study aimed to compare the sirolimus-eluting BiOSS LIM C dedicated coronary bifurcation stent with second-generation -limus drug-eluting stents (rDESs) in the treatment of non-left main (non-LM) coronary bifurcation. The deployment of a single stent in the main vessel–main branch across a side branch was the default strategy in all patients. The primary endpoint was the rate of major cardiovascular events (cardiac death, myocardial infarction, and target lesion revascularization) at 48 months. We enrolled 230 patients, allocating 116 patients to the BiOSS LIM C group and 114 patients to the rDES group. Most procedures were elective (BiOSS vs. rDES: 48.3% vs. 59.6%, p = 0.09) and performed in bifurcations within the left anterior descending/diagonal branch (BiOSS vs. rDES: 51.7% vs. 61.4%, p = 0.15). At 48 months, there were no statistically significant differences between the BiOSS and rDES groups in terms of major adverse cardiovascular events (MACE), cardiac death, myocardial infarction (MI), or target lesion revascularization (TLR) as follows: MACEs—18.1% vs. 14.9%, HR 1.36, 95% CI 0.62–2.22, and p = 0.33; cardiac death—4.3% vs. 3.5%, HR 1.23, 95% CI 0.33–4.56, and p = 0.75; MI—2.6% vs. 3.5%, HR 0.73, 95% CI 0.17–3.23, and p = 0.68; and TLR—11.2% vs. 7.9%, HR 1.66, 95% CI 0.75–3.71, and p = 0.21. The implantation success rate of the BiOSS LIM C stent was very high, and the cumulative MACE rates were promising. The POLBOS 3 trial sets an important benchmark for treating non-LM coronary bifurcations (ClinicalTrials.gov NCT03548272). Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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12 pages, 1023 KiB

Open AccessArticle

Electrical Activity Changes and Neurovascular Unit Markers in the Brains of Patients after Cardiac Surgery: Effects of Multi-Task Cognitive Training

by Irina Tarasova, Irina Kukhareva, Darya Kupriyanova, Tatjana Temnikova, Evgenia Gorbatovskaya and Olga Trubnikova

Biomedicines 2024, 12(4), 756; https://doi.org/10.3390/biomedicines12040756 - 28 Mar 2024

Cited by 1 | Viewed by 1275

Abstract

Background: There is growing interest in finding methods to enhance cognitive function and comprehend the neurophysiological mechanisms that underlie these improvements. It is assumed that non-pharmacological interventions have better results in cognitive recovery. The aim of this study was to assess the effect [...] Read more.

Background: There is growing interest in finding methods to enhance cognitive function and comprehend the neurophysiological mechanisms that underlie these improvements. It is assumed that non-pharmacological interventions have better results in cognitive recovery. The aim of this study was to assess the effect of multi-task cognitive training (MTT) on electroencephalographic (EEG) changes and markers of the neurovascular unit in patients undergoing coronary artery bypass grafting (CABG). Methods: This prospective cohort study involved 62 CABG patients aged 45–75 years, 30 of whom underwent a 5–7-day MTT course. The groups of patients were comparable with respect to baseline clinical and anamnestic characteristics. An EEG study was performed before surgery and 11–12 days after CABG. Markers of the neurovascular unit (S100β, NSE, and BDNF) were examined at three time points: before surgery, within the first 24 h after surgery, and 11–12 days after CABG. Results: Patients without training demonstrated higher relative theta power changes compared to the MTT patients. The course of MTT was associated with low plasma S100β concentration but high BDNF levels at the end of the training course. Conclusions: The theta activity changes and the markers of the neurovascular unit (S100β, BDNF) indicated that the severity of brain damage in cardiac surgery patients after a short course of MTT was slightly reduced. Electrical brain activity indicators and vascular markers can be informative for monitoring the process of cognitive rehabilitation in cardiac surgery patients. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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14 pages, 986 KiB

Open AccessArticle

Artificial Intelligence Applied to Electrical and Non-Invasive Hemodynamic Markers in Elderly Decompensated Chronic Heart Failure Patients

by Gianfranco Piccirillo, Federica Moscucci, Martina Mezzadri, Cristina Caltabiano, Giovanni Cisaria, Guendalina Vizza, Valerio De Santis, Marco Giuffrè, Sara Stefano, Claudia Scinicariello, Myriam Carnovale, Andrea Corrao, Ilaria Lospinuso, Susanna Sciomer and Pietro Rossi

Biomedicines 2024, 12(4), 716; https://doi.org/10.3390/biomedicines12040716 - 22 Mar 2024

Viewed by 1830

Abstract

Objectives: The first aim of this study was to assess the predictive power of Tend interval (Te) and non-invasive hemodynamic markers, based on bioimpedance in decompensated chronic heart failure (CHF). The second one was to verify the possible differences in repolarization and hemodynamic [...] Read more.

Objectives: The first aim of this study was to assess the predictive power of Tend interval (Te) and non-invasive hemodynamic markers, based on bioimpedance in decompensated chronic heart failure (CHF). The second one was to verify the possible differences in repolarization and hemodynamic data between CHF patients grouped by level of left ventricular ejection fraction (LVEF). Finally, we wanted to check if repolarization and hemodynamic data changed with clinical improvement or worsening in CHF patients. Methods: Two hundred and forty-three decompensated CHF patients were studied by 5 min ECG recordings to determine the mean and standard deviation (Te_SD) of Te (first study). In a subgroup of 129 patients (second study), non-invasive hemodynamic and repolarization data were recorded for further evaluation. Results: Total in-hospital and cardiovascular mortality rates were respectively 19 and 9%. Te was higher in the deceased than in surviving subjects (Te: 120 ± 28 vs. 100 ± 25 ms) and multivariable logistic regression analysis reported that Te was related to an increase of total (χ²: 35.45, odds ratio: 1.03, 95% confidence limit: 1.02–1.05, p < 0.001) and cardiovascular mortality (χ²: 32.58, odds ratio: 1.04, 95% confidence limit: 1.02–1.06, p < 0.001). Subjects with heart failure with reduced ejection fraction (HFrEF) reported higher levels of repolarization and lower non-invasive systolic hemodynamic data in comparison to those with preserved ejection fraction (HFpEF). In the subgroup, patients with the NT-proBNP reduction after therapy showed a lower rate of Te, heart rate, blood pressures, contractility index, and left ventricular ejection time in comparison with the patients without NT-proBNP reduction. Conclusion: Electrical signals from ECG and bioimpedance were capable of monitoring the patients with advanced decompensated CHF. These simple, inexpensive, non-invasive, easily repeatable, and transmissible markers could represent a tool to remotely monitor and to intercept the possible worsening of these patients early by machine learning and artificial intelligence tools. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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Review

Jump to: Research, Other

21 pages, 310 KiB

Open AccessReview

The Safety and Efficacy of Dietary Epigallocatechin Gallate Supplementation for the Management of Obesity and Non-Alcoholic Fatty Liver Disease: Recent Updates

by Ruike Yan and Yanli Cao

Biomedicines 2025, 13(1), 206; https://doi.org/10.3390/biomedicines13010206 - 15 Jan 2025

Viewed by 576

Abstract

Epigallocatechin gallate (EGCG) is the predominant bioactive catechin in green tea, and it has been ascribed a range of beneficial health effects. Current increases in obesity and non-alcoholic fatty liver disease (NAFLD) rates represent a persistent and burdensome threat to global public health. [...] Read more.

Epigallocatechin gallate (EGCG) is the predominant bioactive catechin in green tea, and it has been ascribed a range of beneficial health effects. Current increases in obesity and non-alcoholic fatty liver disease (NAFLD) rates represent a persistent and burdensome threat to global public health. While many clinical studies have demonstrated that EGCG is associated with positive effects on various health parameters, including metabolic biomarkers, waist circumference, and body weight when consumed by individuals affected by obesity and NAFLD, there are also some reports suggesting that it may entail some degree of hepatotoxicity. The present review provides a comprehensive summary of the extant clinical findings pertaining to the safety and effectiveness of EGCG in managing obesity and NAFLD, with a particular focus on how treatment duration and dose level affect the bioactivity of this compound. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

21 pages, 1325 KiB

Open AccessReview

Weight Loss Therapies and Hypertension Benefits

by Vasiliki Katsi, Eleni Manta, Christos Fragoulis and Konstantinos Tsioufis

Biomedicines 2024, 12(10), 2293; https://doi.org/10.3390/biomedicines12102293 - 10 Oct 2024

Cited by 1 | Viewed by 1804

Abstract

Obesity and hypertension have become an international health issue, with detrimental consequences on patients. Obesity and hypertension share common pathophysiological mechanisms, such as overactivity of the renin–angiotensin–aldosterone and the sympathetic nervous systems, insulin resistance, and disruption of the leptin pathway. Approved therapies for [...] Read more.

Obesity and hypertension have become an international health issue, with detrimental consequences on patients. Obesity and hypertension share common pathophysiological mechanisms, such as overactivity of the renin–angiotensin–aldosterone and the sympathetic nervous systems, insulin resistance, and disruption of the leptin pathway. Approved therapies for obesity and overweight include phentermine/topiramate, orlistat, naltrexone/bupropion, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide, tirzepatide, and bariatric surgery. This review gives the clinical data in a thorough manner and explains in detail how each of the previously mentioned therapies affects blood pressure levels. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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12 pages, 533 KiB

Open AccessReview

The Role of Ranolazine in the Treatment of Ventricular Tachycardia and Atrial Fibrillation: A Narrative Review of the Clinical Evidence

by Kyosuke Murai, Amir Vasigh, Tamás Alexy, Kálmán Tóth and László Czopf

Biomedicines 2024, 12(8), 1669; https://doi.org/10.3390/biomedicines12081669 - 26 Jul 2024

Viewed by 2072

Abstract

Cardiac arrhythmias are among the leading causes of morbidity and mortality worldwide. While antiarrhythmic drugs traditionally represent the first-line management strategy, their use is often limited by profound proarrhythmic effects. Several studies, including randomized control trials (RCTs), have demonstrated the antiarrhythmic efficacy of [...] Read more.

Cardiac arrhythmias are among the leading causes of morbidity and mortality worldwide. While antiarrhythmic drugs traditionally represent the first-line management strategy, their use is often limited by profound proarrhythmic effects. Several studies, including randomized control trials (RCTs), have demonstrated the antiarrhythmic efficacy of ranolazine, which is registered as an antianginal agent, while also establishing its safety profile. This review compiles clinical evidence investigating the antiarrhythmic properties of ranolazine, focusing primarily on ventricular tachycardia (VT) and atrial fibrillation (AF), as they are common rhythm abnormalities with serious complications. Data from RCTs indicate that ranolazine reduces VT incidence, although this effect is not universal. Therefore, we attempt to better describe the patient population that gains the most benefit from ranolazine due to VT suppression. Additionally, ranolazine is known to enhance the conversion rate of AF to sinus rhythm when combined with other antiarrhythmic drugs such as amiodarone, highlighting its synergistic effect in the atrium without provoking ventricular dysrhythmias. Despite the heterogeneity in the currently available data, ranolazine appears to be an effective and safe option for the management of various arrhythmias. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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33 pages, 8008 KiB

Open AccessReview

Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review

by Diana-Aurora Arnautu, Dragos Cozma, Ioan-Radu Lala, Sergiu-Florin Arnautu, Mirela-Cleopatra Tomescu and Minodora Andor

Biomedicines 2024, 12(8), 1643; https://doi.org/10.3390/biomedicines12081643 - 24 Jul 2024

Viewed by 1104

Abstract

Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. [...] Read more.

Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. Cardiomyopathies frequently result from genetic factors, and the study of heart failure genetics is advancing quickly. Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, encompassing both genetic and nongenetic abnormalities. It is distinguished by the enlargement of the left ventricle or both ventricles, accompanied by reduced contractility. The discovery of the molecular origins and subsequent awareness of the molecular mechanism is broadening our knowledge of DCM development. Additionally, it emphasizes the complicated nature of DCM and the necessity to formulate several different strategies to address the diverse underlying factors contributing to this disease. Genetic variants that can be transmitted from one generation to another can be a significant contributor to causing family or sporadic hereditary DCM. Genetic variants also play a significant role in determining susceptibility for acquired triggers for DCM. The genetic causes of DCM can have a large range of phenotypic expressions. It is crucial to select patients who are most probable to gain advantages from genetic testing. The purpose of this research is to emphasize the significance of identifying genetic DCM, the relationships between genotype and phenotype, risk assessment, and personalized therapy for both those affected and their relatives. This approach is expected to gain importance once treatment is guided by genotype-specific advice and disease-modifying medications. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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22 pages, 3690 KiB

Open AccessReview

New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists

by Ferenc Sztanek, László Imre Tóth, Attila Pető, Marcell Hernyák, Ágnes Diószegi and Mariann Harangi

Biomedicines 2024, 12(6), 1320; https://doi.org/10.3390/biomedicines12061320 - 13 Jun 2024

Cited by 3 | Viewed by 2879

Abstract

Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are [...] Read more.

Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are already available to treat obesity, which can help reduce appetite and/or reduce caloric intake. Incretin-based peptides exert their effect through G-protein-coupled receptors, the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and glucagon peptide hormones are important regulators of insulin secretion and energy metabolism. Understanding the role of intercellular signaling pathways and inflammatory processes is essential for the development of effective pharmacological agents in obesity. GLP-1 receptor agonists have been successfully used, but it is assumed that their effectiveness may be limited by desensitization and downregulation of the target receptor. A growing number of new agents acting on incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may show further significant therapeutic potential. This narrative review summarizes the therapeutic effects of different incretin hormones and presents future prospects in the treatment of T2DM and obesity. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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14 pages, 1148 KiB

Open AccessReview

UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles

by Salvatore Nesci and Speranza Rubattu

Biomedicines 2024, 12(6), 1307; https://doi.org/10.3390/biomedicines12061307 - 13 Jun 2024

Cited by 4 | Viewed by 2602

Abstract

UCP2 is an uncoupling protein homolog to UCP1. Unlike UCP1, which participates in non-shivering thermogenesis by uncoupling oxidative phosphorylation (OXPHOS), UCP2 does not perform a canonical H⁺ leak, consuming the protonmotive force (Δp) through the inner mitochondrial membrane. The UCP2 [...] Read more.

UCP2 is an uncoupling protein homolog to UCP1. Unlike UCP1, which participates in non-shivering thermogenesis by uncoupling oxidative phosphorylation (OXPHOS), UCP2 does not perform a canonical H⁺ leak, consuming the protonmotive force (Δp) through the inner mitochondrial membrane. The UCP2 biological role is elusive. It can counteract oxidative stress, acting with a “mild uncoupling” process to reduce ROS production, and, in fact, UCP2 activities are related to inflammatory processes, triggering pathological conditions. However, the Δp dissipation by UCP2 activity reduces the mitochondrial ATP production and rewires the bioenergetic metabolism of the cells. In all likelihood, UCP2 works as a carrier of metabolites with four carbon atoms (C4), reversing the anaerobic glycolysis-dependent catabolism to OXPHOS. Indeed, UCP2 can perform catalysis in dual mode: mild uncoupling of OXPHOS and metabolite C4 exchange of mitochondria. In vivo, the UCP2 features in the biology of mitochondria promote healthy ageing, increased lifespan, and can assure cerebro- and cardiovascular protection. However, the pathological conditions responsible for insulin secretion suppression are dependent on UCP2 activity. On balance, the uncertain biochemical mechanisms dependent on UCP2 do not allow us to depict the protective role in mitochondrial bioenergetics. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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16 pages, 1592 KiB

Open AccessReview

The Role of Lipoprotein(a) in Peripheral Artery Disease

by Nicholas Pavlatos and Dinesh K. Kalra

Biomedicines 2024, 12(6), 1229; https://doi.org/10.3390/biomedicines12061229 - 1 Jun 2024

Cited by 1 | Viewed by 1533

Abstract

Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated [...] Read more.

Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated 20% of the global population having elevated lipoprotein(a) levels, testing remains underutilized due to poor awareness and a historical lack of effective and safe therapies. Although lipoprotein(a) has a strong association with coronary artery disease and cerebrovascular disease, its relationship with peripheral artery disease is less well established. In this article, we review the epidemiology, biology, and pathogenesis of lipoprotein(a) as it relates to peripheral artery disease. We also discuss emerging treatment options to help mitigate major adverse cardiac and limb events in this population. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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27 pages, 1257 KiB

Open AccessReview

Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine

by Ramcharan Singh Angom and Naga Malleswara Rao Nakka

Biomedicines 2024, 12(3), 693; https://doi.org/10.3390/biomedicines12030693 - 20 Mar 2024

Cited by 13 | Viewed by 6315

Abstract

The zebrafish (Danio rerio) has emerged as an appreciated and versatile model organism for studying cardiovascular and metabolic diseases, offering unique advantages for both basic research and drug discovery. The genetic conservation between zebrafish and humans and their high fecundity and [...] Read more.

The zebrafish (Danio rerio) has emerged as an appreciated and versatile model organism for studying cardiovascular and metabolic diseases, offering unique advantages for both basic research and drug discovery. The genetic conservation between zebrafish and humans and their high fecundity and transparent embryos allow for efficient large-scale genetic and drug-oriented screening studies. Zebrafish possess a simplified cardiovascular system that shares similarities with mammals, making them particularly suitable for modeling various aspects of heart development, function, and disease. The transparency of zebrafish embryos enables the real-time visualization of cardiovascular dynamics, offering insights into early embryonic events and facilitating the study of heart-related anomalies. In metabolic research, zebrafish provide a cost-effective platform for modeling obesity, type 2 diabetes, hyperlipidemia, and other metabolic disorders. Their high reproductive rate allows for the generation of large cohorts for robust statistical analyses, while advanced genetic tools, such as CRISPR/Cas9, enable precise gene editing with which to model specific genetic mutations associated with human diseases. Zebrafish metabolic models have been instrumental in elucidating the molecular mechanisms underlying metabolic diseases, studying the effects of environmental factors, and identifying potential therapeutic targets. Additionally, the permeability of zebrafish embryos to small molecules facilitates drug discovery and screening, offering a rapid and economical approach to identifying compounds with therapeutic potential. In conclusion, zebrafish cardiovascular and metabolic disease models continue to contribute significantly to our perception of disease pathogenesis, providing a platform for translational research and developing novel therapeutic interventions. The versatility, scalability, and genetic manipulability of zebrafish position them as an invaluable asset in unraveling the complexities of cardiovascular and metabolic diseases. This review presents an overview of the zebrafish model’s key features and contributions to investigating cardiovascular and metabolic disorders. We discuss the benefits and drawbacks of using zebrafish models to study human disease and the critical findings revealed by the progress in this endeavor to date. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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Open AccessSystematic Review

Systematic Review of Left Ventricular Remodeling in Response to Hypoglycemic Medications: Assessing Changes in End-Systolic and End-Diastolic Diameters

by Bogdan-Flaviu Buz, Rodica Anamaria Negrean, Florina Caruntu, Tudor Parvanescu, Milena Slovenski, Mirela Cleopatra Tomescu and Diana-Aurora Arnautu

Biomedicines 2024, 12(8), 1791; https://doi.org/10.3390/biomedicines12081791 - 7 Aug 2024

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Hypoglycemic medications are widely used in managing diabetes mellitus, with emerging evidence suggesting their role in cardiac reverse remodeling. This systematic review aims to quantitatively synthesize data regarding the impact of these medications on left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), [...] Read more.

Hypoglycemic medications are widely used in managing diabetes mellitus, with emerging evidence suggesting their role in cardiac reverse remodeling. This systematic review aims to quantitatively synthesize data regarding the impact of these medications on left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), and to evaluate the clinical relevance of these changes in promoting favorable cardiac outcomes. We conducted a comprehensive search across PubMed, Scopus, and the Web of Science up to 22 April 2024, selecting studies based on inclusion criteria that focused on the impact of hypoglycemic medications on LVEDD and LVESD in patients with diabetes. Studies were selected through a rigorous process, adhering to PRISMA guidelines, and involving various designs including randomized controlled trials and observational studies. The main outcomes were changes in LVEDD and LVESD measured by validated cardiac imaging techniques. A total of ten studies met the inclusion criteria, involving a total of 1180 patients. Treatment durations ranged from 3 to 24 months. Significant improvements in cardiac dimensions were noted with some medications. For instance, Liraglutide treatment over three months significantly improved LVEF from 47.2% to 57.2% and reduced LVEDD and LVESD from 46.5 mm to 45.2 mm and 35.2 mm to 32.7 mm, respectively. In contrast, other medications like Sitagliptin showed minimal impact over 24 months. On average, hypoglycemic medications reduced LVEDD from 58.2 mm to 55.0 mm and LVESD from 48.3 mm to 44.3 mm, with a mean improvement in LVEF from 38.9% to 43.8%. Hypoglycemic medications contribute variably to cardiac reverse remodeling. Medications such as Liraglutide and Dapagliflozin demonstrate significant potential in improving cardiac dimensions and function, indicating their utility beyond glycemic control. This review highlights the need for tailored treatment approaches to maximize cardiac outcomes in patients with diabetes, suggesting a broader therapeutic role for these agents. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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Open AccessBrief Report

Effect of Hypoglycemia and Rebound Hyperglycemia on Proteomic Cardiovascular Risk Biomarkers

by Manjula Nandakumar, Thozhukat Sathyapalan, Stephen L. Atkin and Alexandra E. Butler

Biomedicines 2024, 12(6), 1137; https://doi.org/10.3390/biomedicines12061137 - 21 May 2024

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Introduction: Hypoglycemia has been associated with cardiovascular events, and glucose variability has been suggested to be associated with increased cardiovascular risk. Therefore, in this study, we examined the effect on proteomic cardiovascular risk protein markers of (i) mild iatrogenic hypoglycemia and (ii) [...] Read more.

Introduction: Hypoglycemia has been associated with cardiovascular events, and glucose variability has been suggested to be associated with increased cardiovascular risk. Therefore, in this study, we examined the effect on proteomic cardiovascular risk protein markers of (i) mild iatrogenic hypoglycemia and (ii) severe iatrogenic hypoglycemia followed by rebound hyperglycemia. Methods: Two iatrogenic hypoglycemia studies were compared; firstly, mild hypoglycemia in 18 subjects (10 type 2 diabetes (T2D), 8 controls; blood glucose to 2.8 mmoL/L (50 mg/dL) for 1 h), and secondly, severe hypoglycemia in 46 subjects (23 T2D, 23 controls; blood glucose to <2.2 mmoL/L (<40 mg/dL) transiently followed by intravenous glucose reversal giving rebound hyperglycemia). A SOMAscan assay was used to measure 54 of the 92 cardiovascular protein biomarkers that reflect biomarkers involved in inflammation, cellular metabolic processes, cell adhesion, and immune response and complement activation. Results: Baseline to euglycemia showed no change in any of the proteins measured in the T2D cohort. With severe hypoglycemia, the study controls showed an increase in Angiopoietin 1 (ANGPT1) (p < 0.01) and Dickkopf-1 (DKK1) (p < 0.01), but no changes were seen with mild hypoglycemia. In both the mild and severe hypoglycemia studies, at the point of hypoglycemia, T2D subjects showed suppression of Brother of CDO (BOC) (p < 0.01). At 1 h post-hypoglycemia, the changes in ANGPT1, DKK1, and BOC had resolved, with no additional protein biomarker changes despite rebound hyperglycemia from 1.8 ± 0.1 to 12.2 ± 2.0 mmol/L. Conclusions: Proteomic biomarkers of cardiovascular disease showed changes at hypoglycemia that resolved within 1 h following the hypoglycemic event and with no changes following hyperglycemia rebound, suggesting that any cardiovascular risk increase is due to the hypoglycemia and not due to glucose fluctuation per se. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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