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Search Results (193)

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Keywords = renin–angiotensin–aldosterone system (RAAS)

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18 pages, 634 KiB  
Review
Cardiorenal Syndrome: Molecular Pathways Linking Cardiovascular Dysfunction and Chronic Kidney Disease Progression
by Fabian Vasquez, Caterina Tiscornia, Enrique Lorca-Ponce, Valeria Aicardi and Sofia Vasquez
Int. J. Mol. Sci. 2025, 26(15), 7440; https://doi.org/10.3390/ijms26157440 - 1 Aug 2025
Viewed by 131
Abstract
Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to [...] Read more.
Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article
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17 pages, 1682 KiB  
Review
High-Fructose-Induced Salt-Sensitive Hypertension: The Potential Benefit of SGLT4 or SGLT5 Modulation
by Sharif Hasan Siddiqui and Noreen F. Rossi
Nutrients 2025, 17(15), 2511; https://doi.org/10.3390/nu17152511 - 30 Jul 2025
Viewed by 218
Abstract
Hypertension is an important risk factor for cardiovascular diseases. High salt intake when consumed with excess fructose enhances hypertension and resultant cardiovascular disease. Usually, the small intestine absorbs dietary fructose, and the proximal tubule of kidney reabsorbs filtered fructose into the circulation with [...] Read more.
Hypertension is an important risk factor for cardiovascular diseases. High salt intake when consumed with excess fructose enhances hypertension and resultant cardiovascular disease. Usually, the small intestine absorbs dietary fructose, and the proximal tubule of kidney reabsorbs filtered fructose into the circulation with the help of different transporters including SGLT4 and SGLT5. Very recently, SGLT5 mRNA has also been found to be expressed in the heart. High-fructose diet stimulates the sympathetic nervous system and renin–angiotensin–aldosterone (RAAS) activity, of which both are responsible for endothelial dysfunction and are associated with salt-sensitive hypertension. Few studies exist regarding the effects of SGLT4 and SGLT5 on cardiovascular function and blood pressure. However, SGLT4 gene knockout does not alter fructose-associated impact on blood pressure. In contrast, blood pressure does not increase in SGLT5 knockout rats even during fructose consumption. Given that limiting fructose and salt consumption as a public health strategy has proven challenging, we hope that studies into SGLT4 and SGLT5 transporters will open new research initiatives to address salt-sensitive hypertension and cardiovascular disease. This review highlights current information about SGLT4 and SGLT5 on fructose absorption, salt-sensitive hypertension, cardiovascular disease and points the way for the development of therapeutic fructose inhibitors that limit adverse effects. Full article
(This article belongs to the Special Issue Effects of Nutrient Intake on Cardiovascular Disease)
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10 pages, 439 KiB  
Article
Comparison of Angiotensin II (Giapreza®) Use in Kidney Transplantation Between Black and Non-Black Patients
by Michelle Tsai, Jamie Benken, Joshua Adisumarta, Eleanor Anderson, Chris Cheng, Adriana Ortiz, Enrico Benedetti, Hokuto Nishioka and Scott Benken
Biomedicines 2025, 13(8), 1819; https://doi.org/10.3390/biomedicines13081819 - 24 Jul 2025
Viewed by 368
Abstract
Background/Objectives: Perioperative hypotension during kidney transplantation poses a risk to graft function and survival. Angiotensin II (AngII) is an endogenous vasoconstrictor targeting the renin–angiotensin–aldosterone system (RAAS) to increase blood pressure. Black patients may have a different response to synthetic angiotensin II (AT2S) [...] Read more.
Background/Objectives: Perioperative hypotension during kidney transplantation poses a risk to graft function and survival. Angiotensin II (AngII) is an endogenous vasoconstrictor targeting the renin–angiotensin–aldosterone system (RAAS) to increase blood pressure. Black patients may have a different response to synthetic angiotensin II (AT2S) compared to non-Black patients, given differential expressions in renin profiles. The purpose of this study is to assess the difference between Black and non-Black patients in total vasopressor duration and usage when AT2S is first line for hypotension during kidney transplantation. Methods: A single-center, retrospective cohort study comparing Black and non-Black patients who required AT2S as a first-line vasopressor for hypotension during the perioperative period of kidney transplantation. Results: The primary outcome evaluating total usage of vasopressors found that Black patients required longer durations of vasopressors (36.9 ± 66.8 h vs. 23.7 ± 31.7 h; p = 0.022) but no difference in vasopressor amount (0.07 ± 0.1 NEE vs. 0.05 ± 0.1 NEE; p = 0.128) compared to non-Black patients. Regression analysis found that body weight was associated with the duration of vasopressors (p < 0.05), while baseline systolic blood pressure was inversely associated with it. Longer duration of vasopressors and duration of transplant surgery were associated with delayed graft function in regression analysis (p < 0.05). Conclusions: Black patients had a longer duration of vasopressors, but this was not driven by differences in usage of AT2S. As baseline weight was significantly higher in Black patients and associated with duration of usage, perhaps the metabolic differences in our Black patients led to the observed differences. Regardless, longer durations of vasopressors were associated with delayed graft function, making this an area of utmost importance for continued investigation. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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19 pages, 1204 KiB  
Review
Immunomodulatory Effects of RAAS Inhibitors: Beyond Hypertension and Heart Failure
by Raluca Ecaterina Haliga, Elena Cojocaru, Oana Sîrbu, Ilinca Hrițcu, Raluca Elena Alexa, Ioana Bianca Haliga, Victorița Șorodoc and Adorata Elena Coman
Biomedicines 2025, 13(7), 1779; https://doi.org/10.3390/biomedicines13071779 - 21 Jul 2025
Viewed by 466
Abstract
The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use [...] Read more.
The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Cardiovascular Biology, 2nd Edition)
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15 pages, 1455 KiB  
Article
Assessment of Selected Biochemical Parameters of the Renin–Angiotensin–Aldosterone System in Repeat Convalescent Plasma Donors in the Context of Long-Term Changes Following SARS-CoV-2 Infection
by Marta Stanek, Dorota Diakowska, Krzysztof Kaliszewski and Anna Leśków
J. Clin. Med. 2025, 14(14), 4910; https://doi.org/10.3390/jcm14144910 - 10 Jul 2025
Viewed by 284
Abstract
Background: SARS-CoV-2 infection has been associated with long-term health consequences, including dysregulation of the renin–angiotensin–aldosterone system (RAAS). This study aimed to evaluate long-term changes in selected RAAS-related biochemical parameters in repeat convalescent plasma donors, focusing on enzymes and peptides involved in vascular regulation [...] Read more.
Background: SARS-CoV-2 infection has been associated with long-term health consequences, including dysregulation of the renin–angiotensin–aldosterone system (RAAS). This study aimed to evaluate long-term changes in selected RAAS-related biochemical parameters in repeat convalescent plasma donors, focusing on enzymes and peptides involved in vascular regulation and inflammation. Methods: Thirty repeat convalescent plasma donors were enrolled, each providing four serum samples at defined time points post-infection. Samples were collected during Period 1 (≤60 days), Period 2 (61–90 days), Period 3 (91–120 days), and Period 4 (>120 days) after confirmed SARS-CoV-2 infection. The analyzed parameters included angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1–7 (Ang 1–7), angiotensin 1–9 (Ang 1–9), ACE, ACE2, ADAM10, and ADAM17. Concentrations were determined using ELISA assays. The control group consisted of pre-pandemic serum samples from healthy individuals. Results: An initial post-infection increase was observed in most parameters, particularly in Period 1. Over time, levels of several markers declined, yet Ang 1–7 and Ang 1–9 remained elevated compared to controls even beyond 120 days. Significant correlations (p < 0.05) were found between ADAM10, ADAM17, and angiotensin peptides, suggesting prolonged RAAS modulation. Metalloproteinases were notably elevated early after infection, potentially contributing to inflammatory and cardiovascular responses. Conclusions: The findings indicate a transient but measurable biochemical response of the RAAS following SARS-CoV-2 infection, with most parameters normalizing after 120 days. However, the sustained elevation of certain markers suggests a potential long-term impact on vascular homeostasis, warranting further investigation. Full article
(This article belongs to the Special Issue Post-COVID Symptoms and Causes, 3rd Edition)
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15 pages, 2783 KiB  
Review
Angiotensin II and Cardiovascular Disease: Balancing Pathogenic and Protective Pathways
by Ulvi Bayraktutan
Curr. Issues Mol. Biol. 2025, 47(7), 501; https://doi.org/10.3390/cimb47070501 - 1 Jul 2025
Viewed by 417
Abstract
The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or [...] Read more.
The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or type 2 (AT2R) receptors. AT1R activation promotes vasoconstriction, oxidative stress, endothelial dysfunction, peripheral vascular resistance, and atherosclerosis, all of which substantially contribute to cellular senescence and organismal ageing. Conversely, AT2R activation counteracts these effects by inducing vascular relaxation and attenuating vascular cell proliferation and migration, offering protection against occlusive vascular disease. Additionally, conversion of angiotensin II to angiotensin (1-7) or angiotensin I to angiotensin (1-9) by ACE2 provides further cardiovascular protection by lowering oxidative stress, inflammation, and abnormal cell growth. Bearing these in mind, measures to control angiotensin II synthesis or receptor activity have been at the forefront of antihypertensive treatment. This paper briefly reviews the RAAS and explores the dual role of angiotensin II in promoting disease and mediating vascular protection, with a focus on its impact on ageing and cardiovascular pathology. Full article
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11 pages, 225 KiB  
Article
Acute Kidney Injury After Peripheral Interventions Using Carbon Dioxide Angiography—Risk Factors Beyond Iodinated Contrast Media
by Tim Wittig, Sarah Fischer, Birte Winther, Andrej Schmidt, Dierk Scheinert, Anne Hoffmann and Sabine Steiner
Life 2025, 15(7), 1046; https://doi.org/10.3390/life15071046 - 30 Jun 2025
Viewed by 438
Abstract
Contrast-associated acute kidney injury (CA-AKI) is a known complication of endovascular procedures using an iodinated contrast medium (ICM), especially in patients with peripheral artery disease (PAD) and chronic kidney disease (CKD). This retrospective study evaluated the incidence and risk factors of AKI in [...] Read more.
Contrast-associated acute kidney injury (CA-AKI) is a known complication of endovascular procedures using an iodinated contrast medium (ICM), especially in patients with peripheral artery disease (PAD) and chronic kidney disease (CKD). This retrospective study evaluated the incidence and risk factors of AKI in patients with PAD and CKD undergoing diagnostic angiography or endovascular intervention using carbon dioxide (CO2) as the primary contrast medium, with optional bailout ICM use. We included 340 patients who underwent peripheral angiography or intervention between September 2014 and December 2020. CO2 was used as the primary contrast medium for all patients, as the majority were classified with advanced CKD stages 3–5 according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Bailout ICM was used in 80% of cases (mean 21.23 ± 14.09 mL). Postinterventional AKI occurred in 13.2% of patients, with over 70% classified as stage 1. Seven patients required new dialysis within 7 days. Multivariate analysis identified hypertension, heart failure, and coronary artery disease as independent AKI risk factors. Statin or Renin–Angiotensin–Aldosteron System (RAAS) inhibitor use and higher pre-interventional GFR were protective. AKI remains common in patients undergoing CO2-guided peripheral procedures. Further studies are needed to explore underlying mechanisms and outcomes. Full article
(This article belongs to the Special Issue Advances in Endovascular Therapies and Acute Stroke Management)
26 pages, 3581 KiB  
Article
Differential Effects of Losartan and Finerenone on Diabetic Remodeling, Oxidative Stress and ACE Activity in the Gastrointestinal Tract of Streptozotocin-Induced Diabetic Rats
by Marisa Esteves-Monteiro, Cláudia Vitorino-Oliveira, Joana Castanheira-Moreira, Mariana Ferreira-Duarte, Patrícia Dias-Pereira, Vera Marisa Costa, Manuela Morato and Margarida Duarte-Araújo
Int. J. Mol. Sci. 2025, 26(13), 6294; https://doi.org/10.3390/ijms26136294 - 29 Jun 2025
Viewed by 407
Abstract
Gastrointestinal (GI) complications are common in diabetes, but the role of the local renin-angiotensin-aldosterone system (RAAS) in gut remodeling remains unclear. This study examined histomorphometric alterations, oxidative stress, and systemic and tissue-specific angiotensin converting enzyme (ACE) and ACE2 activity in streptozotocin (STZ)-induced diabetic [...] Read more.
Gastrointestinal (GI) complications are common in diabetes, but the role of the local renin-angiotensin-aldosterone system (RAAS) in gut remodeling remains unclear. This study examined histomorphometric alterations, oxidative stress, and systemic and tissue-specific angiotensin converting enzyme (ACE) and ACE2 activity in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats (n = 24) were assigned to control (CTRL), diabetic (STZ), and diabetic groups treated with losartan (STZ-LOS, 20 mg/kg/day) or finerenone (STZ-FIN, 10 mg/kg/day). After 14 days, gut samples were collected from the stomach, duodenum, jejunum, ileum, and colon for histology, glutathione measurements (GSH/GSSG), and ACE/ACE2 activity assessment. Diabetic rats exhibited increased GI wall thickness—particularly in the mucosal and muscular layers—elevated GSSG levels, and a reduced GSH/GSSG ratio. Losartan prevented these changes, whereas finerenone did not produce a significant effect. Circulating ACE and ACE2 levels were elevated, but the ACE2/ACE ratio remained unchanged. Locally, ACE activity increased across gut segments, whereas ACE2 remained stable, lowering the ACE2/ACE ratio, particularly in the duodenum and jejunum. The Z-FHL/h-HL ratio was above 1 across segments but decreased in these same regions (jejunum and duodenum). These findings highlight the protective role of losartan against diabetic GI remodeling via AT1R blockade and suggest complex, segment-specific RAAS regulation in diabetic gut pathology. Full article
(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition))
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19 pages, 786 KiB  
Review
Cardiovascular Risk and Its Presentation in Chronic Kidney Disease
by Stefan J. Schunk and Paul Zimmermann
J. Clin. Med. 2025, 14(13), 4567; https://doi.org/10.3390/jcm14134567 - 27 Jun 2025
Viewed by 964
Abstract
Background/Objectives: Patients with chronic kidney disease (CKD) are associated with a significantly elevated cardiovascular risk. The incidence and prevalence of mediated cardiac disorders and major adverse cardiac events (MACEs), such as heart failure, arrhythmias, acute coronary syndrome (ACS) based on coronary artery [...] Read more.
Background/Objectives: Patients with chronic kidney disease (CKD) are associated with a significantly elevated cardiovascular risk. The incidence and prevalence of mediated cardiac disorders and major adverse cardiac events (MACEs), such as heart failure, arrhythmias, acute coronary syndrome (ACS) based on coronary artery disease (CAD), stroke, venous thromboembolism, and peripheral artery disease, are significantly higher in CKD patients as compared with the general population. Methods: This narrative review summarizes the current clinical understanding, the pathophysiological mechanisms, and the clinical consequences in the context of cardiovascular risk and disease in CKD. Results: The impact of CKD on mediated cardiovascular disorders and elevated MACE prevalence is complex and multifactorial. The underlying mechanisms involve various traditional cardiovascular risk factors, such as arterial hypertension, smoking, dyslipidemia, and diabetes. Furthermore, CKD-specific molecular and pathophysiological factors, such as chronic inflammation and associated oxidative stress and endothelial cell dysfunction, pro-coagulatory status, uremic toxins and uremic lipids, progressive vascular calcification, and alterations in the regulation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic activation cause an increased cardiovascular risk. Conclusions: Understanding the complex disease mechanisms between CKD and elevated cardiovascular risk might contribute to optimizing individual patients’ risk stratification and result in individualized diagnostic and treatment strategies via appropriate clinical biomarker application and individualized anti-inflammatory approaches. Full article
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19 pages, 3862 KiB  
Article
Characterization of Novel ACE-Inhibitory Peptides from Nemopilema nomurai Jellyfish Venom Hydrolysate: In Vitro and In Silico Approaches
by Ramachandran Loganathan Mohan Prakash, Deva Asirvatham Ravi, Du Hyeon Hwang, Changkeun Kang and Euikyung Kim
Mar. Drugs 2025, 23(7), 267; https://doi.org/10.3390/md23070267 - 26 Jun 2025
Viewed by 528
Abstract
The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. [...] Read more.
The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. In this study, we conducted a detailed biochemical and computational characterization of these peptides. The IC50 values were determined to be 23.81 µM for IVGRPLANG and 5.68 µM for IGDEPRHQYL. Kinetic analysis using Lineweaver–Burk plots revealed that both peptides act as competitive ACE inhibitors, with calculated inhibition constants (Ki) of 51.38 µM and 5.45 µM, respectively. To assess the structural stability of the ACE–peptide complexes, molecular dynamics simulations were performed. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses provided insights into complex stability, while interaction fraction analysis elucidated key bond types and residue–ligand contacts involved in binding. Furthermore, a network pharmacology approach was employed to predict therapeutic targets within the renin–angiotensin–aldosterone system (RAAS). Eleven target proteins were identified: IVGRPLANG was associated with REN, ACE, CTSB, CTSS, and AGTR2; IGDEPRHQYL was linked to REN, AGT, AGTR1, AGTR2, KNG1, and BDKR2. Molecular docking analyses using HADDOCK software (version 2.4) were conducted for all targets to evaluate binding affinities, providing further insight into the peptides’ therapeutic potential. Full article
(This article belongs to the Special Issue Jellyfish-Derived Compounds)
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19 pages, 1309 KiB  
Review
Implications of Oxidative Stress in the Pathophysiological Pathways of Heart Failure
by Andrea D’Amato, Claudia Cestiè, Federico Ferranti, Camilla Segato, Silvia Prosperi, Rosanna Germanò, Vincenzo Myftari, Simona Bartimoccia, Valentina Castellani, Roberto Badagliacca, Vittoria Cammisotto, Pasquale Pignatelli, Carmine Dario Vizza and Paolo Severino
Int. J. Mol. Sci. 2025, 26(11), 5165; https://doi.org/10.3390/ijms26115165 - 28 May 2025
Viewed by 713
Abstract
Heart failure (HF) is a major socioeconomic problem worldwide, associated with high morbidity and mortality due to several underlying diseases. HF is driven by several closely linked mechanisms whose effects are mutually reinforcing. Some of the signalling pathways involved in the progression of [...] Read more.
Heart failure (HF) is a major socioeconomic problem worldwide, associated with high morbidity and mortality due to several underlying diseases. HF is driven by several closely linked mechanisms whose effects are mutually reinforcing. Some of the signalling pathways involved in the progression of HF may initially be compensatory, such as the renin–angiotensin–aldosterone system (RAAS), whose hyperactivation plays a central role in the progression of HF by promoting fluid retention, inflammation, oxidative stress (OS), and myocardial dysfunction. Fluid retention is also promoted by the action of neprilysin, which contrasts natriuresis and vasodilation. Among the compensatory and subsequently maladaptive systems, chronic hyperactivation of the sympathetic nervous system (SNS) exacerbates maladaptive remodelling and drives the progression of HF. At the molecular level, mitochondrial dysfunction and inflammatory substances are involved in the development of a state of systemic oxidative stress and inflammation. The aim of the following manuscript was to revise the pathophysiology and role of OS in HF, focusing on the current knowledge of the molecular pathways involved. Full article
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63 pages, 3510 KiB  
Review
Morphometric and Molecular Interplay in Hypertension-Induced Cardiac Remodeling with an Emphasis on the Potential Therapeutic Implications
by Lyubomir Gaydarski, Kristina Petrova, Stancho Stanchev, Dimitar Pelinkov, Alexandar Iliev, Iva N. Dimitrova, Vidin Kirkov, Boycho Landzhov and Nikola Stamenov
Int. J. Mol. Sci. 2025, 26(9), 4022; https://doi.org/10.3390/ijms26094022 - 24 Apr 2025
Cited by 1 | Viewed by 1184
Abstract
Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in [...] Read more.
Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin–angiotensin–aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH4) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life. Full article
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28 pages, 5892 KiB  
Review
Cardiovascular–Kidney–Metabolic Syndrome: A New Paradigm in Clinical Medicine or Going Back to Basics?
by Victoria Mutruc, Cristina Bologa, Victorița Șorodoc, Alexandr Ceasovschih, Bianca Codrina Morărașu, Laurențiu Șorodoc, Oana Elena Catar and Cătălina Lionte
J. Clin. Med. 2025, 14(8), 2833; https://doi.org/10.3390/jcm14082833 - 19 Apr 2025
Cited by 3 | Viewed by 3466
Abstract
Cardiovascular, renal, and metabolic diseases are pathophysiologically interdependent, posing a significant global health challenge and being associated with a substantial increase in morbidity and mortality. In 2023, the American Heart Association (AHA) defined this complex network of interconnected health conditions as the cardiovascular–kidney–metabolic [...] Read more.
Cardiovascular, renal, and metabolic diseases are pathophysiologically interdependent, posing a significant global health challenge and being associated with a substantial increase in morbidity and mortality. In 2023, the American Heart Association (AHA) defined this complex network of interconnected health conditions as the cardiovascular–kidney–metabolic (CKM) syndrome. This syndrome is based on common pathophysiological mechanisms, including chronic inflammation, oxidative stress, hyperglycemia and insulin resistance, activation of the renin–angiotensin–aldosterone system (RAAS), and neurohormonal dysfunction, which trigger a vicious cycle where the impairment of one organ contributes to the progressive deterioration of the others. An integrated approach to these conditions, rather than treating them as separate entities, supports a holistic management strategy that helps to reduce the burden on public health and improve patients’ quality of life. Existing management focuses on lifestyle modification, glycemic and lipid control, and the use of nephroprotective and cardioprotective therapies. This narrative review aims to synthesize and contextualize existing information on the complex interactions between these systems and on diagnostic approaches, as well as to provide an overview of the available therapeutic options. Full article
(This article belongs to the Section Cardiovascular Medicine)
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25 pages, 1673 KiB  
Review
Gut Microbiota in Heart Failure—The Role of Inflammation
by Petros N. Fountoulakis, Panagiotis Theofilis, Panayotis K. Vlachakis, Paschalis Karakasis, Konstantinos Pamporis, Marios Sagris, Yannis Dimitroglou, Panagiotis Tsioufis, Evangelos Oikonomou, Konstantinos Tsioufis and Dimitris Tousoulis
Biomedicines 2025, 13(4), 911; https://doi.org/10.3390/biomedicines13040911 - 9 Apr 2025
Cited by 2 | Viewed by 2660
Abstract
Heart failure (HF) has become an immense health concern affecting almost 1–2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin–Angiotensin–Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. [...] Read more.
Heart failure (HF) has become an immense health concern affecting almost 1–2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin–Angiotensin–Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. The recent literature points towards the interaction between the intestinal flora and the heart, also called the gut–heart axis. The human gastrointestinal tract is naturally inhabited by various microbes, which are distinct for each patient, regulating the functions of many organs. Alterations of the gut microbiome, a process called dysbiosis, may result in systemic diseases and have been associated with heart failure through inflammatory and autoimmune mechanisms. The disorder of intestinal permeability favors the translocation of microbes and many metabolites capable of inducing inflammation, thus further contributing to the deterioration of normal cardiac function. Besides diet modifications and exercise training, many studies have revealed possible gut microbiota targeted treatments for managing heart failure. The aim of this review is to demonstrate the impact of the inflammatory environment induced by the gut microbiome and its metabolites on heart failure and the elucidation of these novel therapeutic approaches. Full article
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23 pages, 642 KiB  
Review
Cardiac Remodeling and Arrhythmic Burden in Pre-Transplant Cirrhotic Patients: Pathophysiological Mechanisms and Management Strategies
by Charilila-Loukia Ververeli, Yannis Dimitroglou, Stergios Soulaidopoulos, Evangelos Cholongitas, Constantina Aggeli, Konstantinos Tsioufis and Dimitris Tousoulis
Biomedicines 2025, 13(4), 812; https://doi.org/10.3390/biomedicines13040812 - 28 Mar 2025
Viewed by 916
Abstract
Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a [...] Read more.
Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin–angiotensin–aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes. Full article
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