Biomedicines

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19 pages, 2284 KB

Open AccessArticle

H₂S Donor Therapy Reverses Established Pulmonary Arterial Hypertension and Pulmonary Vascular Structural Remodeling in Rats

by Jie Zheng, Yanan Zhang, Boyang Lv, Yuanyuan Ma, Xuecong Zhong, Junbao Du, Hongfang Jin and Yaqian Huang

Biomedicines 2026, 14(4), 760; https://doi.org/10.3390/biomedicines14040760 - 26 Mar 2026

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Abstract

Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H₂S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H₂S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary [...] Read more.

Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H₂S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H₂S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary vascular structural remodeling is unknown. In this study, we aimed to test whether H₂S donor therapy can reverse the existing PAH in a chronic-hypoxia rat model. Methods: After 3 weeks of hypoxia exposure, rats with established hypoxia-induced pulmonary hypertension (HPH) were randomized to receive either continued hypoxia alone or hypoxia plus the H₂S donor NaHS (56 μmol/kg·d, ip) for an additional 6 weeks. Pulmonary artery pressure, pulmonary artery muscularization, and right ventricular hypertrophy were assessed. Furthermore, the cell proliferation (Ki-67 and PCNA), ERK1/2 phosphorylation, and persulfidation of the endothelin type A receptor (ETAR) were examined and detected in rat lung tissues and pulmonary artery smooth muscle cells (PASMCs). Results: H₂S therapy effectively reversed established HPH and pulmonary artery structural remodeling, reducing RVSP, mPAP, and the proportion of fully muscularized small pulmonary arteries by 13.8%, 12.0%, and 62.7%, respectively. Moreover, the PAT/PET ratio was normalized to normoxic levels. The right ventricular hypertrophy index decreased by 29.2%. Mechanistically, H₂S therapy suppressed PASMC proliferation, reduced ERK1/2 phosphorylation, and enhanced ETAR persulfidation. Furthermore, dithiothreitol-mediated reduction of ETAR persulfidation abrogated these antiproliferative effects of H₂S therapy, establishing persulfidation as an obligatory mechanism. Conclusions: H₂S donor therapy effectively reverses established HPH and pulmonary vascular structural remodeling by inhibiting PASMC proliferation, which is linked to enhanced ETAR persulfidation. These data provide preclinical proof-of-concept for H₂S-based interventions in patients with manifest PAH. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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14 pages, 797 KB

Open AccessArticle

Cardiorenal and Metabolic Convergence in Acute Heart Failure: Severe Cardiorenometabolic Syndrome as a High-Risk Phenotype

by Raquel López-Vilella, Borja Guerrero Cervera, Julia Martínez Solé, Sara Huélamo Montoro, Víctor Donoso Trenado, Mireia Company Langa, Valero Soriano Alfonso, Luis Martínez Dolz and Luis Almenar-Bonet

Biomedicines 2026, 14(2), 467; https://doi.org/10.3390/biomedicines14020467 - 20 Feb 2026

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Abstract

Background: Cardiorenometabolic syndrome (CRMS) reflects the interaction between heart failure (HF), chronic kidney disease, and metabolic disorders. Its prognostic impact during the acute phase of HF remains poorly defined. The primary objective of this study was to assess whether severe CRMS (sCRMS: estimated [...] Read more.

Background: Cardiorenometabolic syndrome (CRMS) reflects the interaction between heart failure (HF), chronic kidney disease, and metabolic disorders. Its prognostic impact during the acute phase of HF remains poorly defined. The primary objective of this study was to assess whether severe CRMS (sCRMS: estimated glomerular filtration rate <45 mL/min/1.73 m² associated with type 2 diabetes mellitus and/or obesity) predicts worse clinical outcomes. Methods: This was a retrospective observational study of a prospective cohort including 2228 patients admitted for acute HF between 2015 and 2025. Clinical characteristics and outcomes (mortality, HF readmission, and the composite endpoint) were compared between patients with and without sCRMS. Results: sCRMS was present in 486 patients (21.8%) who were older, had worse functional class, and a higher burden of cardiovascular comorbidities. They presented more frequently with systemic congestion and less often with de novo HF. During follow-up, sCRMS was associated with higher mortality (29.4% vs. 18.4%), HF readmissions (56.2% vs. 33.5%), and the composite endpoint (85.6% vs. 51.9%) (all p < 0.001). In multivariable analysis, sCRMS remained an independent predictor of mortality (HR 1.25), readmissions (HR 1.24), and overall morbidity and mortality (HR 1.20). Conclusions: In patients hospitalized for acute HF, sCRMS consistently identified a clinically vulnerable phenotype with an unfavorable prognosis. These findings support the value of sCRMS as a simple and reproducible prognostic marker and highlight the need for integrated cardiorenometabolic strategies during post-discharge follow-up. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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18 pages, 4295 KB

Open AccessArticle

Vascular Contractile and Structural Properties in Diet-Induced Atherosclerosis-Prone CB₁-LDL Receptor Double Knockout Animal Model

by Kinga Shenker-Horváth, Zsolt Vass, Bálint Bányai, Stella Kiss, Kinga Bernadett Kovács, Judit Kiss, Andrea Petra Trenka, Janka Borbála Gém, Annamária Szénási, Eszter Mária Horváth, Zoltán Jakus, György L. Nádasy, Gabriella Dörnyei and Mária Szekeres

Biomedicines 2026, 14(2), 284; https://doi.org/10.3390/biomedicines14020284 - 27 Jan 2026

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Abstract

Background: Atherosclerosis forms the background of several cardiovascular pathologies. LDL receptor knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels. Previously we found that vasodilation responses in HFD LDLR-KO mice were improved in the absence of type 1 [...] Read more.

Background: Atherosclerosis forms the background of several cardiovascular pathologies. LDL receptor knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels. Previously we found that vasodilation responses in HFD LDLR-KO mice were improved in the absence of type 1 cannabinoid receptors (CB₁Rs). We aimed to reveal the effects of HFD and CB₁Rs on vascular contractile and structural properties. Methods: Experiments were performed on LDLR-CB₁R double knockout and wild type (WT) mice, kept on an HFD or control diet (CD) for 5 months. Thoracic aortas were isolated for Oil Red plaque staining and abdominal aorta segments for myography to obtain phenylephrine (Phe)-induced (100 nM–10 µM) contractile responses. Aorta samples were subjected to histology stainings with hematoxylin–eosin and resorcin–fuchsin (elastin density) and for smooth muscle actin (SMA) immunohistochemistry. Results: Phe-induced contractions significantly increased in HFD groups (p < 0.05) similarly in all genotypes. However, contractions were stronger with CD in CB₁R-KO compared to WT. Plaque areas were increased in LDLR-KO mice compared to WT, significant in HFD groups (p < 0.05). SMA increased to HFD, while elastin density remained similar, with the highest value in double KO-HFD. Intima/media ratio significantly decreased in double KO-HFD vs. CD. Conclusions: Our results indicate that HFD-treated LDLR-KO mice develop atherosclerosis with functional contractile and structural alterations modulated by CB₁Rs: absence of CB₁Rs elicited higher contraction properties with some modification in vascular remodeling indicating contribution of the CB₁R to cellular signalization controlling wall thickness and elasticity in pathological conditions. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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15 pages, 1738 KB

Open AccessArticle

Optical Coherence Tomography Angiography in Type 1 Diabetes Mellitus. Report 5: Cardiovascular Risk

by Josep Rosinés-Fonoll, Ruben Martin-Pinardel, Sonia Marias-Perez, Xavier Suarez-Valero, Silvia Feu-Basilio, Sara Marín-Martinez, Carolina Bernal-Morales, Rafael Castro-Dominguez, Andrea Mendez-Mourelle, Cristian Oliva, Irene Vila, Teresa Hernández, Irene Vinagre, Manel Mateu-Salat, Emilio Ortega, Marga Gimenez and Javier Zarranz-Ventura

Biomedicines 2026, 14(1), 153; https://doi.org/10.3390/biomedicines14010153 - 11 Jan 2026

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Abstract

Objectives: This study aimed to investigate the association between optical coherence tomography angiography (OCTA) parameters and cardiovascular (CV) risk scores in individuals with type 1 diabetes (T1D). Methods: A cross-sectional analysis of a large-scale prospective OCTA trial cohort (ClinicalTrials.gov NCT03422965) was [...] Read more.

Objectives: This study aimed to investigate the association between optical coherence tomography angiography (OCTA) parameters and cardiovascular (CV) risk scores in individuals with type 1 diabetes (T1D). Methods: A cross-sectional analysis of a large-scale prospective OCTA trial cohort (ClinicalTrials.gov NCT03422965) was performed. Demographic, systemic, and ocular data—including OCTA imaging—were collected. T1D participants were stratified into three CV risk categories: moderate (MR), high (HR), and very high risk (VHR). Individualized predictions for fatal and non-fatal CV events at 5 and 10 years were calculated using the STENO T1 Risk Engine calculator. Results: A total of 501 individuals (1 eye/patient; 397 T1D, 104 controls) were included. Subjects with MR (n = 37), HR (n = 152) and VHR (n = 208) exhibited significantly reduced vessel density (VD) (20.9 ± 1.3 vs. 20.2 ± 1.6 vs. 19.3 ± 1.8 mm⁻¹, p < 0.05), perfusion density (PD) (0.37 ± 0.02 vs. 0.36 ± 0.02 vs. 0.35 ± 0.02%, p < 0.05) and foveal avascular zone circularity (0.69 ± 0.06 vs. 0.65 ± 0.07 vs. 0.63 ± 0.09, p < 0.05). Statistically significant negative correlations were observed between CV risk and OCTA parameters including VD, PD, and retinal nerve fiber layer thickness, while central macular thickness (CMT) showed a positive correlation (p < 0.05). Notably, CMT was significantly associated with 5-year CV risk. Conclusions: OCTA-derived metrics, particularly reduced retinal VD and PD, are associated with elevated CV risk scores in T1D patients. These findings suggest that OCTA may serve as a valuable non-invasive tool for identifying individuals with increased CV risk scores. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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18 pages, 3073 KB

Open AccessArticle

Role of Circulating Lipids in Mediating the Diabetogenic Effect of Obesity

by Yutang Wang, Yan Fang, Fadi J. Charchar, Grant R. Drummond and Christopher G. Sobey

Biomedicines 2026, 14(1), 11; https://doi.org/10.3390/biomedicines14010011 - 20 Dec 2025

Cited by 1 | Viewed by 748

Abstract

Background/Objectives: Obesity is a major risk factor for diabetes, but the underlying mechanisms remain incompletely understood. Obesity is associated with alterations in circulating lipids. This study aimed to determine whether, and to what extent, circulating lipids mediate the diabetogenic effect of obesity. [...] Read more.

Background/Objectives: Obesity is a major risk factor for diabetes, but the underlying mechanisms remain incompletely understood. Obesity is associated with alterations in circulating lipids. This study aimed to determine whether, and to what extent, circulating lipids mediate the diabetogenic effect of obesity. Methods: This mediation analysis included 26,627 adult participants. Parallel mediation analysis included total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides as simultaneous mediators. Low-density lipoprotein (LDL) cholesterol was excluded from the parallel model due to collinearity with total cholesterol and was assessed separately using simple mediation analysis adjusted for confounders. Results: After adjustment for tested confounders, parallel mediation analysis showed that increases in triglycerides and reductions in HDL cholesterol mediated 24.0% (indirect effect coefficient = 0.23; 95% CI: 0.20–0.26; p < 0.05) and 3.8% (indirect effect coefficient = 0.04; 95% CI: 0.01–0.06; p < 0.05) of the diabetogenic effect of obesity, respectively. An increase in total cholesterol modestly attenuated the diabetogenic effect of obesity by 2.3% (indirect effect coefficient = −0.02; 95% CI: −0.03 to −0.01; p < 0.05), a magnitude that is unlikely to be clinically meaningful. Simple mediation analysis indicated that LDL cholesterol was not a significant mediator. Conclusions: Triglycerides are the most influential circulating lipid in mediating the diabetogenic effect of obesity, accounting for 24% of the total effect. Targeting triglyceride levels might represent an underrecognized therapeutic strategy to reduce obesity-related diabetes risk. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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22 pages, 22628 KB

Open AccessArticle

Comparative Hepatoprotective Effects of Dapagliflozin and Trimetazidine in Diabetic Rats with Doxorubicin-Induced Liver Injury

by Enver Ciftel, Omer Satiroglu, Muhammed Mursel Ogutveren, Tolga Mercantepe, Sibel Mataraci Karakas, Omer Genc, Adnan Yilmaz and Filiz Mercantepe

Biomedicines 2025, 13(11), 2633; https://doi.org/10.3390/biomedicines13112633 - 27 Oct 2025

Cited by 2 | Viewed by 1361

Abstract

Background: Diabetes mellitus and cancer often coexist, increasing the risk of liver injury. Doxorubicin (DOXO) is a widely used antineoplastic drug with known hepatotoxic effects. Dapagliflozin (DAPA) and trimetazidine (TMZ) have been reported to exert hepatoprotective actions, but their combined effects remain unclear. [...] Read more.

Background: Diabetes mellitus and cancer often coexist, increasing the risk of liver injury. Doxorubicin (DOXO) is a widely used antineoplastic drug with known hepatotoxic effects. Dapagliflozin (DAPA) and trimetazidine (TMZ) have been reported to exert hepatoprotective actions, but their combined effects remain unclear. Methods: Forty-eight male Sprague Dawley rats were allocated into six groups: control, streptozotocin (STZ), STZ + DOXO, STZ + DOXO + DAPA, STZ + DOXO + TMZ, and STZ + DOXO + DAPA + TMZ. Liver injury was assessed by histopathology, oxidative stress markers (MDA, GSH), and immunohistochemistry (Tumor Necrosis Factor-alpha (TNF-α), 8-Hydroxy-2′-deoxyguanosine (8-OHdG), Caspase-3, Transforming Growth Factor-beta 1 (TGF-β1), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Nuclear Factor kappa-B/p65 (NF-κB/p65)). Results: STZ and STZ + doxorubicin groups developed marked hepatic injury. Unexpectedly, the STZ + doxorubicin group showed lower alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, along with reduced Malondialdehyde (MDA) and elevated glutathione (GSH), suggesting compensatory antioxidant and apoptotic responses. Dapagliflozin more effectively normalized transaminases and reduced oxidative DNA damage, whereas trimetazidine exerted stronger effects on MDA, GSH, and inflammatory markers. The combination provided additive but not consistently superior benefits. Immunohistochemical analyses confirmed these findings, showing attenuated expression of TNF-α, 8-OHdG, caspase-3, and TGF-β1 and reduced TUNEL-positive hepatocytes and NF-κB/p65 immunoreactivity following treatment, indicating coordinated anti-apoptotic and anti-inflammatory effects. Conclusions: Dapagliflozin and trimetazidine each attenuated diabetes- and doxorubicin-related hepatic injury through partly distinct mechanisms, with the combination providing additive but not consistently superior effects. These findings suggest a potential hepatoprotective role for both agents; however, the clinical implications remain uncertain and require confirmation in further mechanistic and translational studies. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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20 pages, 2063 KB

Open AccessArticle

The Association of Elevated Factor VIII and von Willebrand Factor (vWF) Levels with SYNTAX Score in Patients with Chronic Coronary Syndrome

by Predrag Djuric, Zorica Mladenovic, Zoran Jovic, Snjezana Vukotic, Marijan Spasic, Mirjana Mijuskovic, Brankica Terzic, Zoran Radojicic, Nina Radisavljevic, Marko Djuric and Dragan Djuric

Biomedicines 2025, 13(9), 2284; https://doi.org/10.3390/biomedicines13092284 - 17 Sep 2025

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Abstract

Background and Objectives: Factor VIII (FVIII) and the von Willebrand factor (vWF) are key components of hemostatic balance. Disruption of the vWF-ADAMTS13 axis, characterized by elevated vWF and reduced ADAMTS13 activity has been implicated in thrombotic disorders, including COVID-19-asscoiated coagulopathy, where this imbalance [...] Read more.

Background and Objectives: Factor VIII (FVIII) and the von Willebrand factor (vWF) are key components of hemostatic balance. Disruption of the vWF-ADAMTS13 axis, characterized by elevated vWF and reduced ADAMTS13 activity has been implicated in thrombotic disorders, including COVID-19-asscoiated coagulopathy, where this imbalance correlates with disease severity and mortality. This study evaluated the relationship between plasma FVIII and vWF levels and the severity of coronary artery disease (CAD), as assessed by the SYNTAX score. Methods: We enrolled 82 patients with chronic coronary syndrome (CCS) and a positive treadmill test who underwent elective coronary angiography. Based on the SYNTAX score, patients were divided into three groups: Group I (≤22), Group II (23–32), and Group III (≥33). Results: FVIII levels varied significantly (Group I: 2.25 ± 0.75; Group III: 2.97 ± 0.95; p = 0.007), with an OR of 3.632 (95% CI: 1.116–11.826; p = 0.03). vWF levels differed significantly across SYNTAX groups (Group I: 1.16 ± 0.59; Group II: 1.52 ± 0.62; Group III: 1.49 ± 0.80; p = 0.040). vWF > 1.75 was more frequent in Groups II and III, with an odds ratio (OR) of 4.909 (95% CI: 1.429–16.864; p = 0.01) for Group III vs. Group I. Fibrinogen and C-reactive protein (CRP) were elevated in patients with SYNTAX scores ≥33. In multinomial logistic regression analysis, FVIII emerged as the sole independent predictor of CAD complexity (p = 0.004), while the vWF showed significance in pairwise comparison (Group II vs. Group I; OR = 3.433, p = 0.049). Conclusions: This study demonstrated significant differences in hemostatic and inflammatory biomarkers across SYNTAX score categories reflecting CAD severity in CCS patients. FVIII emerged as an independent predictor of CAD complexity, while the vWF demonstrated significant associations in specific subgroup comparisons. The observed vWF-ADAMTS13 axis dysregulation supports the rationale for investigating vWF-targeted therapeutics, including agents such as caplacizumab, in cardiovascular disease management. These findings require validation in larger studies. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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10 pages, 580 KB

Open AccessArticle

MIBG Scintigraphy and Arrhythmic Risk in Myocarditis

by Maria Lo Monaco, Margherita Licastro, Matteo Nardin, Rocco Mollace, Flavia Nicoli, Alessandro Nudi, Giuseppe Medolago and Erika Bertella

Biomedicines 2025, 13(8), 1981; https://doi.org/10.3390/biomedicines13081981 - 15 Aug 2025

Cited by 1 | Viewed by 1149

Abstract

Background: The widespread use of cardiac magnetic resonance imaging (MRI) in clinical practice has enabled the identification of numerous patients with evident damage from previous myocarditis, whether known or unknown. For years, myocardial fibrosis has been a topic of interest due to its [...] Read more.

Background: The widespread use of cardiac magnetic resonance imaging (MRI) in clinical practice has enabled the identification of numerous patients with evident damage from previous myocarditis, whether known or unknown. For years, myocardial fibrosis has been a topic of interest due to its established correlation with arrhythmic events in various clinical settings, including ischemic heart disease, dilated cardiomyopathy, and hypertrophic cardiomyopathy. MIBG scintigraphy is a method widely used in patients who are candidates for defibrillator implantation or have experienced heart failure. This examination evaluates the sympathetic innervation of the myocardium. Objective: To assess the real arrhythmogenic risk of non-ischemic scars identified in symptomatic or asymptomatic patients through the use of MIBG. Methods: Patients were retrospectively selected based on the presence of non-ischemic myocardial fibrosis detected by cardiac MRI, consistent with a myocarditis outcome (even in the absence of a clear history of myocarditis). These patients underwent myocardial scintigraphy with MIBG using a tomographic technique. Results: A total of 50 patients (41 males, mean age 51 ± 16 years) who underwent MRI from 2019 to June 2024 were selected. The primary indication for MRI was ventricular ectopic extrasystoles detected on Holter ECG (n = 12, 54%), while five patients underwent MRI following a known acute infectious event (23%, including three cases of COVID-19 infection). All symptomatic patients presented with chest pain in the acute phase, accompanied by elevated hsTNI levels (mean value: 437 pg/mL). The MRI findings showed normal ventricular volumes (LV: 80 mL/m², RV: 81 mL/m²) and normal ejection fractions (56% and 53%, respectively). The mean native T1 mapping value was 1013 ms (normal range: 950–1050). T2 mapping values were altered in the 5 patients who underwent MRI during the acute phase (mean value: 57 ms), without segmentation. Additionally, three patients had non-tamponade pericardial effusion. All patients exhibited LGE (nine subepicardial, seven midwall, six patchy). All patients underwent myocardial scintigraphy with MIBG at least 6 months after the acute event, with only one case yielding a positive result. This patient, a 57-year-old male, had the most severe clinical presentation, including more than 65,000 premature ventricular beats (PVBs) and multiple episodes of paroxysmal supraventricular tachycardia (PSVT) recorded on Holter ECG. MRI findings showed severe left ventricular dysfunction, a slightly dilated LV, and midwall LGE at the septum, coinciding with hypokinetic areas. Conclusions: MIBG scintigraphy could be a useful tool in assessing arrhythmic risk in patients with previous myocarditis. It could help reduce the clinical burden of incidental findings of non-ischemic LGE, which does not appear to be independently associated with an increased risk profile. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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14 pages, 1385 KB

Open AccessArticle

Is TGF-β Associated with Cytokines and Other Biochemical or Clinical Risk Parameters in Early-Onset CAD Patients?

by Bartosz Rakoczy, Violetta Dziedziejko, Krzysztof Safranow and Monika Rac

Biomedicines 2025, 13(8), 1840; https://doi.org/10.3390/biomedicines13081840 - 29 Jul 2025

Cited by 1 | Viewed by 1399

Abstract

Background: TGF-β is an immunosuppressive cytokine. Its signaling pathway plays a role in anti-inflammatory responses. Coronary artery disease (CAD) is a clinical consequence of atherosclerosis, which manifests as chronic inflammation and involves platelet mediators, including TGF-β. The aim of this study is to [...] Read more.

Background: TGF-β is an immunosuppressive cytokine. Its signaling pathway plays a role in anti-inflammatory responses. Coronary artery disease (CAD) is a clinical consequence of atherosclerosis, which manifests as chronic inflammation and involves platelet mediators, including TGF-β. The aim of this study is to validate the diagnostic utility of TGF-β levels in relation to classical and molecular risk factors for CAD. Methods: The study group included 25 women and 75 men, all aged up to 55 and 50 years, respectively, who had been diagnosed with early-onset CAD. Fasting blood samples were taken to measure plasma levels of TGF-β, sCD36, PCSK9, TNF, VEGF, IL-6, and E-selectin using the ELISA method. Furthermore, a full lipid profile, apolipoproteins (Lp(a), ApoA1, and ApoB), C-reactive protein (hsCRP), and blood morphology were analyzed at the Central Hospital Laboratory. A physical examination was also performed. Results: Positive associations were observed between TGF-β concentration and TNF, platelet count, PTC, and triglyceride levels. TNF and platelet concentration were significant independent predictors of increased plasma TGF-β levels. None of the clinical parameters showed statistically significant associations with plasma TGF-β concentration. Conclusions: Our research has demonstrated that TGF-β levels, including circulating TNF, triglycerides, and platelets, are linked to specific biochemical risk factors in early-onset CAD cases. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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11 pages, 779 KB

Open AccessArticle

Effects of Ellagic Acid on Myocardial Contractility in Isolated and Perfused Rat Hearts

by Giada Benedetti, Leonardo Carbonetti, Vincenzo Calderone and Lara Testai

Biomedicines 2025, 13(7), 1645; https://doi.org/10.3390/biomedicines13071645 - 4 Jul 2025

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Abstract

Background/Objectives: Ellagic acid (EA) is a polyphenol found in several fruits and vegetables, including pomegranate, nuts and berries. It exhibits significant health benefits, mainly cardio- and vaso-protective; indeed, EA protects the myocardium against infarction and inhibits cardiac fibrosis. These beneficial effects may [...] Read more.

Background/Objectives: Ellagic acid (EA) is a polyphenol found in several fruits and vegetables, including pomegranate, nuts and berries. It exhibits significant health benefits, mainly cardio- and vaso-protective; indeed, EA protects the myocardium against infarction and inhibits cardiac fibrosis. These beneficial effects may be, at least in part, promoted by calcium release from and uptake by the sarcoplasmic reticulum, which are crucial events for cardiac relaxation and contraction. Regardless, the exact mechanism is currently unclear. Methods: A deeper investigation of the role of EA in cardiac contractility and the underlying mechanism has been carried out by using an ex vivo model of isolated and perfused rat heart. Results and Discussion: EA perfusion (100 nM–10 µM) did not influence the coronary flow (CF), suggesting the absence of a vasoactivity, but significantly increased contractility parameters (LVDP and dP/dt). Interestingly, a more marked effect of EA on LVDP and dP/dt values was observed when it was perfused in the presence of AngII. Cyclopiazonic acid (CA) and red ruthenium (RR), specific antagonists of SERCA and RyRs, respectively, were used to explore the contribution of EA when the intracellular calcium handling was altered. In the presence of CA, EA, perfused at increasing concentrations, showed a very modest positive inotropism (significant only at 1 µM). Instead, RR, which significantly compromised all functional parameters, completely masked the effects of EA; furthermore, a marked reduction in CF and a dramatic impact on the positive inotropism occurred. Conclusions: These results demonstrate the positive inotropism of EA on isolated and perfused hearts and suggest that the RyRs may be a main target through which EA plays its effects, since inhibition with RR almost completely blocks the positive inotropism. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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14 pages, 259 KB

Open AccessArticle

Markers of Vascular Function and Future Coronary Artery Disease Risk Among Malaysians with Individual Cardiovascular Risk Factors

by Amilia Aminuddin, Nina Diyana Rusanuar, Md Rizman Md Lazin Md Lazim, Azizah Ugusman, Izzat Zulhilmi Abd Rahman, Kalaivani Chellappan, Mohd Shawal Faizal Mohamad, Wan Amir Nizam Wan Ahmad and Wan Yus Haniff Wan Isa

Biomedicines 2025, 13(4), 899; https://doi.org/10.3390/biomedicines13040899 - 8 Apr 2025

Cited by 2 | Viewed by 1505

Abstract

Background/Objectives: Vascular function measurements, including central parameters [pulse wave velocity (PWV) and augmentation index (AI)], as well as peripheral measures [finger photoplethysmography fitness index (PPGF)], have been introduced to detect early vascular damage associated with coronary artery disease (CAD) risk factors. This study [...] Read more.

Background/Objectives: Vascular function measurements, including central parameters [pulse wave velocity (PWV) and augmentation index (AI)], as well as peripheral measures [finger photoplethysmography fitness index (PPGF)], have been introduced to detect early vascular damage associated with coronary artery disease (CAD) risk factors. This study aimed to compare peripheral and central vascular function marker levels among subjects with hypertension (HPT), dyslipidemia, and obesity. We also aimed to determine the relationship between these markers and CAD risk factors among these groups. Methods: A total of 320 subjects including healthy individuals and those with CAD risk factors were recruited. Peripheral vascular function was assessed using the PPGF, whereas central vascular markers included measurements of PWV and AI. The Framingham risk score (FRS) was calculated using an online calculator. Results: The mean age of the subjects was 33.73 ± 7.29 years. PWV and AI were significantly higher in HPT subjects (8.03 ± 1.40 m/s and 21.90% ± 10.57%) than the control. PPGF levels showed no significant differences between the groups. PWV was associated with FRS in the HPT and dyslipidemia groups, whereas AI was associated with FRS in the obese group. PPGF showed associations with PWV and AI in the dyslipidemia group. Conclusions: PWV and AI serve as robust macrovascular markers indicating arterial stiffness and systemic vascular resistance linked to CAD risk, while PPGF, as a microvascular marker, offers valuable insights into early endothelial dysfunction and microcirculatory anomalies, especially in dyslipidemia subjects. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

20 pages, 2394 KB

Open AccessArticle

From Metabolic Syndrome to Cardio-Kidney-Metabolic Syndrome in the SIMETAP Study: Prevalence Rates of Metabolic Syndrome and Its Independent Associations with Cardio-Renal-Metabolic Disorders Other than Its Defining Criteria

by Antonio Ruiz-García, Ezequiel Arranz-Martínez, Adalberto Serrano-Cumplido, Sergio Cinza-Sanjurjo, Carlos Escobar-Cervantes, José Polo-García and Vicente Pallarés-Carratalá

Biomedicines 2025, 13(3), 590; https://doi.org/10.3390/biomedicines13030590 - 28 Feb 2025

Cited by 2 | Viewed by 2680

Abstract

Background/Objectives: Metabolic syndrome (MetS) is a highly prevalent entity defined according to cardiometabolic criteria. Other disorders related to MetS could help assess the comprehensive risk of diabetes, cardiovascular disease, and chronic kidney disease (CKD). This study aimed to update the prevalence rates [...] Read more.

Background/Objectives: Metabolic syndrome (MetS) is a highly prevalent entity defined according to cardiometabolic criteria. Other disorders related to MetS could help assess the comprehensive risk of diabetes, cardiovascular disease, and chronic kidney disease (CKD). This study aimed to update the prevalence rates of MetS and to assess its relationship with other disorders and clinical conditions other than the criteria defining MetS. Methods: A cross-sectional observational study was conducted with a random population-based sample of 6588 study subjects between 18 and 102 years of age. Crude and sex- and age-adjusted prevalence rates of MetS were calculated, and their associations with comorbidities and clinical conditions other than their defining criteria were assessed by bivariate and multivariate analysis. Results: The adjusted prevalence rates were 36.0% for MetS (39.8% in men; 33.5% in women), 21.5% for premorbid Mets, and 14.5% for morbid MetS. Considering only clinical conditions other than the criteria defining MetS, the independent disorders associated with premorbid MetS were hypercholesterolemia, hypertension, high levels of lipid accumulation product, high triglyceride-glucose index (TyG), high visceral adiposity index, high fatty liver index, and high waist-to-height ratio (WtHR), highlighting excess adiposity (EA). The independent disorders associated with morbid MetS were hypercholesterolaemia, high-WtHR, EA, high-TyG index, heart failure, atrial fibrillation, CKD, and albuminuria, highlighting hypertension. Conclusions: One-fifth of the adult population has premorbid MetS, and almost one-sixth has morbid MetS. Almost two-fifths of people with MetS are at moderate, high, or very high risk of CKD, and four-fifths are at high or very high cardiovascular risk. In addition to the criteria defining MetS, other cardiovascular-renal-metabolic disorders show an independent association with MetS, highlighting EA for premorbid MetS and hypertension for morbid MetS. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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Review

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26 pages, 1636 KB

Open AccessReview

Gene Therapy for Cardiovascular and Cerebrovascular Disease: Mechanisms, Translational Barriers, and the Road Ahead

by Zixu Liu, Ruiqi Liu, Ying Ying and Jing Nie

Biomedicines 2026, 14(5), 1142; https://doi.org/10.3390/biomedicines14051142 - 18 May 2026

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Abstract

Cardiovascular and cerebrovascular diseases, encompassing cardiac arrhythmias, atherosclerosis, and ischaemic stroke, remain the foremost causes of death and long-term disability globally. Despite improved outcomes with conventional therapy, substantial residual risk persists, providing the impetus for gene-based intervention. KCNQ1/KCNH2 suppression-and-replacement, SCN5A base editing, and [...] Read more.

Cardiovascular and cerebrovascular diseases, encompassing cardiac arrhythmias, atherosclerosis, and ischaemic stroke, remain the foremost causes of death and long-term disability globally. Despite improved outcomes with conventional therapy, substantial residual risk persists, providing the impetus for gene-based intervention. KCNQ1/KCNH2 suppression-and-replacement, SCN5A base editing, and structural protein restoration via PKP2 and TMEM43 have each demonstrated capacity to re-establish electrophysiological stability in arrhythmia models. For atherosclerosis, RNA-based agents, notably inclisiran, alongside in vivo editing strategies such as VERVE-101, offer durable lipid reduction and attenuation of vascular inflammation. In ischaemic stroke, cGAS–STING silencing, AAV-NeuroD1-mediated neuronal reprogramming, and delivery of neurotrophic factors, including VEGF and BDNF, extend the therapeutic window well beyond reperfusion. Collectively, these approaches position gene therapy as a meaningful complement to standard care, capable of addressing root molecular pathology rather than downstream consequences. This review synthesises current mechanistic understanding, translational obstacles, and emerging directions across these three disease domains, arguing that, delivery and safety challenges notwithstanding, gene therapy stands to substantially reshape how cardiovascular and cerebrovascular diseases are prevented and treated. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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33 pages, 1321 KB

Open AccessReview

The Emerging Role of Mechanobiology in Connecting Metabolic and Cardiovascular Diseases: From Fundamentals to Future Therapies

by Agnieszka Kowalik, Patrycja Paszenda, Julia Rydzek, Małgorzata Stanios, Julia Soczyńska and Piotr Gajewski

Biomedicines 2026, 14(3), 525; https://doi.org/10.3390/biomedicines14030525 - 26 Feb 2026

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Abstract

Mechanobiology has emerged as a unifying framework for understanding how mechanical forces and tissue physical properties regulate cellular function, metabolism, and disease progression. Mechanical forces are fundamental regulators of cellular behaviour and tissue homeostasis. Growing evidence indicates that disturbances in mechanobiological signalling contribute [...] Read more.

Mechanobiology has emerged as a unifying framework for understanding how mechanical forces and tissue physical properties regulate cellular function, metabolism, and disease progression. Mechanical forces are fundamental regulators of cellular behaviour and tissue homeostasis. Growing evidence indicates that disturbances in mechanobiological signalling contribute to both metabolic disorders and cardiovascular diseases, two highly prevalent and interrelated groups of conditions. This review aims to synthesize current evidence on mechanobiological mechanisms linking metabolic dysfunction and cardiovascular pathology, with particular emphasis on shared pathways involved in tissue remodelling, inflammation, and disease progression. Shared pathogenic mechanisms, including chronic low-grade inflammation, oxidative and endoplasmic reticulum stress, and lipotoxicity, further reinforce the bidirectional relationship between metabolic and cardiovascular disorders. Moreover, advances in mechanobiological imaging and the usage of mechanobiological biomarkers are more commonly regarded as promising tools for early detection of the disease and risk stratification. It is worth mentioning that targeting mechanosensitive pathways may support the development of personalised diagnostic strategies and novel therapeutic approaches addressing both metabolic and cardiovascular components of disease, which may result in a breakthrough. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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24 pages, 1179 KB

Open AccessReview

The Influence of Anesthetics on the Functions of the Endothelium and Oxidative Stress: A Critical Review

by Marko Djuric, Irina Nenadic, Nina Radisavljevic, Dusan Todorovic, Maja Stojanovic, Nemanja Dimic, Marina Bobos, Suzana Bojic, Predrag Stevanovic, Predrag Savic, Dejan Stojakov, Ivan Palibrk and Dragan Djuric

Biomedicines 2025, 13(10), 2357; https://doi.org/10.3390/biomedicines13102357 - 26 Sep 2025

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Abstract

Endothelial dysfunction (characterized by reduced vasodilation or vasoconstriction, oxidative stress, inflammation, and pro-thrombotic condition) is a critical factor in the pathophysiology of various cardiovascular conditions, and the application of anesthetics can affect this dysfunction. Patients undergoing major surgery, especially cardiovascular surgery, are at [...] Read more.

Endothelial dysfunction (characterized by reduced vasodilation or vasoconstriction, oxidative stress, inflammation, and pro-thrombotic condition) is a critical factor in the pathophysiology of various cardiovascular conditions, and the application of anesthetics can affect this dysfunction. Patients undergoing major surgery, especially cardiovascular surgery, are at increased risk of endothelial dysfunction. The impact of anesthetics on endothelial function can vary depending on the specific agent, dosage, duration of exposure, comorbidities, etc. Certain anesthetics, especially at higher doses, may increase the production of reactive oxygen species (ROS), leading to oxidative stress and endothelial dysfunction through reduced nitric oxid (NO) availability. Some anesthetics can modulate inflammatory responses, either by suppressing or exacerbating inflammation, or may affect the permeability of the endothelium, potentially leading to pulmonary edema and disruption of the blood-brain barrier. Anesthetics can influence endothelial glycocalyx. Understanding anesthetics effects is crucial for optimizing anesthetic management, particularly in patients with pre-existing cardiovascular issues. Therefore, the aim of this review is to critically evaluate the effects of different classes of anesthetics on endothelial function and oxidative stress. Specifically, we address how anesthetics influence NO bioavailability, endothelial glycocalyx integrity, inflammatory and oxidative pathways, and clinical outcomes in surgical patients. By summarizing current evidence, we aim to highlight mechanistic insights and identify potential perioperative strategies to minimize endothelial dysfunction. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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22 pages, 930 KB

Open AccessReview

Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity

by Zsolt Szekeres, Eszter Szabados and Anita Pálfi

Biomedicines 2025, 13(8), 1989; https://doi.org/10.3390/biomedicines13081989 - 15 Aug 2025

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Abstract

Objectives: Obesity has become a major health issue, with multifactorial etiologies involving lifestyle, genetic, and neuroendocrine mechanisms. Despite public health campaigns and lifestyle interventions, long-term weight loss is often difficult to achieve or sustain. This literature review aims to summarize current knowledge [...] Read more.

Objectives: Obesity has become a major health issue, with multifactorial etiologies involving lifestyle, genetic, and neuroendocrine mechanisms. Despite public health campaigns and lifestyle interventions, long-term weight loss is often difficult to achieve or sustain. This literature review aims to summarize current knowledge on the main molecular mechanisms that hinder weight loss and to summarize the newest therapeutic strategies targeting obesity. Methods: The literature review was conducted using PubMed, Scopus, and Web of Science databases, with a preference for peer-reviewed original articles, systematic reviews, and meta-analyses. Eligible studies were required to be published in the English language and within the last ten years (2015–2025), with the exception of historically significant publications. A total of 112 articles were included in our review. Results: Obesity is a complex, chronic, recurrent metabolic condition that requires personalized, multidisciplinary treatment approaches. In this review, we summarize the major molecular mechanisms underlying weight gain and weight maintenance in obesity. In this literature review, we address the metabolic memory and epigenetics that act through DNA and histone modifications and micro interfering RNAs, resulting in an energy imbalance that can be passed on to further generations. The dysfunction of adipose tissue contributes to chronic low-grade inflammation and insulin resistance, leading to more severe obesity. The ratio of white, beige, and brown adipocytes also plays an important role in regulating energy balance. Novel medical interventions offer promising results in attenuating these mechanisms against successful weight loss. Conclusions: Current interventions, including calorie restriction, physical activity, and pharmacological treatment together, may show great promise in combating obesity, but long-term efficacy and safety remain to be established. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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19 pages, 925 KB

Open AccessReview

Muscle Wasting and Treatment of Dyslipidemia in COPD: Implications for Patient Management

by Andrea Bianco, Raffaella Pagliaro, Angela Schiattarella, Domenica Francesca Mariniello, Vito D’Agnano, Roberta Cianci, Ersilia Nigro, Aurora Daniele, Filippo Scialò and Fabio Perrotta

Biomedicines 2025, 13(8), 1817; https://doi.org/10.3390/biomedicines13081817 - 24 Jul 2025

Cited by 4 | Viewed by 2811

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial condition associated with significant systemic complications such as cardiovascular disease (CVD), metabolic disorders, muscle wasting, and sarcopenia. While Body Mass Index (BMI) is a well-established indicator of obesity and has prognostic value in COPD, its [...] Read more.

Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial condition associated with significant systemic complications such as cardiovascular disease (CVD), metabolic disorders, muscle wasting, and sarcopenia. While Body Mass Index (BMI) is a well-established indicator of obesity and has prognostic value in COPD, its role in predicting disease outcomes is complex. Muscle wasting is prevalent in COPD patients and exacerbates disease severity, contributing to poor physical performance, reduced quality of life, and increased mortality. Additionally, COPD is linked to metabolic disorders, such as dyslipidemia and diabetes, which contribute to systemic inflammation and worse prognosis and, therefore, should be treated. The systemic inflammatory response plays a central role in the development of sarcopenia. In this review, we highlight the mixed efficacy of statins in managing dyslipidemia in COPD, considering side effects, including muscle toxicity in such a frail population. Alternative lipid-lowering therapies and nutraceuticals, in addition to standard treatment, have the potential to target hypercholesterolemia, which is a coexisting condition present in more than 50% of all COPD patients, without worsening muscle wasting. The interference between adipose tissue and lung, and particularly the potential protective role of adiponectin, an adipocytokine with anti-inflammatory properties, is also reviewed. Respiratory, metabolic and muscular health in COPD is comprehensively assessed. Identifying and managing dyslipidemia and paying attention to other relevant COPD comorbidities, such as sarcopenia and muscle wasting, is important to improve the quality of life and to reduce the clinical burden of COPD patients. Future research should focus on understanding the relationships between these intimate mechanisms to facilitate specific treatment for systemic involvement of COPD. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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10 pages, 250 KB

Open AccessReview

Navigating Sarcopenia Risks in GLP-1RA Therapy for Advanced Heart Failure

by Winston Wang, Danielle Green, Ramzi Ibrahim, Mahmoud Abdelnabi, Hoang Nhat Pham, Beani Forst, Mohamed Allam, Patrick Sarkis, George Bcharah, Juan Farina, Chadi Ayoub, Dan Sorajja and Reza Arsanjani

Biomedicines 2025, 13(5), 1108; https://doi.org/10.3390/biomedicines13051108 - 2 May 2025

Cited by 4 | Viewed by 4562

Abstract

Cardiac cachexia (CC) is a severe complication of advanced heart failure (HF), characterized by involuntary weight loss and muscle wasting, leading to poor outcomes and higher mortality. Despite its severity, CC remains under-recognized and undertreated, lacking targeted therapies specifically addressing its pathophysiology. Glucagon-like [...] Read more.

Cardiac cachexia (CC) is a severe complication of advanced heart failure (HF), characterized by involuntary weight loss and muscle wasting, leading to poor outcomes and higher mortality. Despite its severity, CC remains under-recognized and undertreated, lacking targeted therapies specifically addressing its pathophysiology. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), though beneficial in reducing cardiovascular risk in patients with HF, may exacerbate muscle wasting in cachectic patients, necessitating further investigation. Non-pharmacological strategies, including tailored nutritional support and exercise programs, have shown positive effects on body composition and quality of life in patients with CC. However, there remains a gap in recommendations tailored to preventive strategies and pharmacologic therapies for patients with CC and concomitant GLP-1RA use. This review highlights the multifactorial mechanisms underlying CC and current and emerging therapeutic approaches for mitigating HF-related sarcopenia while on GLP-1RAs. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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20 pages, 1390 KB

Open AccessSystematic Review

Targeting Cardiac Metabolism in Heart Failure with PPARα Agonists: A Review of Preclinical and Clinical Evidence

by Carla Handford, Laura Stirling-Barros, Mahboube Ganji-Arjenaki, Masliza Mahmod, Milad Nazarzadeh and Malgorzata Wamil

Biomedicines 2025, 13(9), 2080; https://doi.org/10.3390/biomedicines13092080 - 26 Aug 2025

Cited by 1 | Viewed by 2756

Abstract

Background and objective: Heart failure (HF) is associated with high morbidity, mortality, and healthcare costs. Its prevalence continues to rise, particularly in the context of ageing populations and increasing rates of metabolic comorbidities such as type 2 diabetes and obesity. We aimed to [...] Read more.

Background and objective: Heart failure (HF) is associated with high morbidity, mortality, and healthcare costs. Its prevalence continues to rise, particularly in the context of ageing populations and increasing rates of metabolic comorbidities such as type 2 diabetes and obesity. We aimed to assess the therapeutic potential of repurposing PPARα agonists for the treatment of HF. Method: We conducted a comprehensive literature review to evaluate preclinical and clinical evidence investigating the potential of PPARα agonist drugs in reducing HF. We did not apply any restrictions on the study design. Results: The current body of evidence consists of preclinical mechanistic studies, emerging pharmacogenetic data, and post hoc analyses of large randomised clinical trials (RCTs) that included HF endpoints. No dedicated, HF-specific RCTs of PPARα agonists were identified. These studies support the hypothesis that PPARα agonists may link metabolic modulation with cardiac remodelling. Preclinical models demonstrate potential therapeutic benefits, such as enhanced myocardial energy metabolism and attenuation of fibrosis and inflammation, as well as context-dependent risks, including possible deleterious effects in advanced HF or off-target mechanisms. Prior failures of fibrates to improve cardiovascular outcomes in some trials and concerns in PPARα-deficient states underscore the complexity of metabolic therapies in HF. These findings support a more stratified, phenotype-driven approach to therapy. RCTs specifically designed to evaluate HF outcomes are essential to clarify whether PPARα agonists can complement established neurohormonal treatments, particularly in the context of the rising burden of HFpEF associated with obesity and type 2 diabetes. Conclusions: PPARα agonists represent a promising class within the emerging therapeutic framework of metabolic heart failure. They are inexpensive, generally well tolerated, and address several pathophysiological mechanisms of HF. Preliminary evidence suggests that fenofibrate may delay or prevent HF in high-risk diabetic populations. However, rigorous, dedicated trials are needed to establish their clinical utility. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—4th Edition)

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