Search Results (248)

Diabetes-related pathophysiological processes contribute to endothelial dysfunction, arterial stiffening (AS), hypertension, vascular remodeling, and impaired myocardial perfusion. This study aimed to assess the relationship between arterial wall parameters and sST2 concentration as potential risk factors in type 2 diabetes (T2DM) and investigate sex-related differences. To achieve this, we enrolled 100 patients with suspected or exacerbated coronary artery disease (CAD) and divided them into a T2DM group (n = 58) and a control group (n = 42). Endothelial reactivity (lnRHI), ABI, sST2 levels, and carotid–femoral (cfPWV) and carotid–radial pulse wave velocity (crPWV) were assessed. Coronary angiography was performed in every patient, and epicardial flow and myocardial perfusion were evaluated using QuBE and FLASH. Our results showed that the coronary angiographic findings were similar in both groups. However, T2DM patients had a significantly higher central AS (cfPWV 10.8 ± 2 vs. 9.9 ± 2.7 m/s, p < 0.05) and vascular age (70.0 ± 12.3 vs. 61.3 ± 15.4 years, p < 0.05), while peripheral AS, RHI, and ABI showed no differences. CfPWV correlated with renal function; higher HbA1c and sST2 levels were additionally associated with advanced vascular age. Notably, central AS and vascular age were higher in men with T2DM but not in women. These findings indicate that T2DM patients exhibit increased central AS and vascular aging, influenced by sST2 levels, suggesting fibrosis as a target for precision medicine in T2DM. Full article

Cardiorenal syndrome (CRS) is a term used to describe the combined dysfunction of the heart and kidneys. This complex disorder is widely acknowledged to be challenging in both its diagnosis and management, and this is the case particularly in the elderly population, due to multi-morbidity, polypharmacy, and age-related physiological changes. Given advancements in medicine and more prolonged cumulative exposure to risk factors in the elderly population, it is likely that the prevalence of chronic kidney disease (CKD) and heart failure (HF) will continue to rise going forward. Hence, understanding the mechanisms involved in the development of CRS is paramount. There are five different CRS types—they are categorised depending on the primary organ involved the acuity of disease. The pathophysiological process behind CRS is complex, involving the interplay of many processes including hemodynamic changes, neurohormonal activation, inflammation, oxidative stress, and endothelial dysfunction and vascular stiffness. The numerous diagnostic and management challenges associated with CRS are significantly further exacerbated in an elderly population. Biomarkers used to aid the diagnosis of CRS, such as serum creatinine and brain natriuretic peptide (BNP), can be challenging to interpret in the elderly population due to age-related renal senescence and multiple comorbidities. Polypharmacy can contribute to the development of CRS and therefore, before initiating treatment, coordinating a patient-centred, multi-speciality, holistic review to assess potential risks versus benefits of prescribed treatments is crucial. The overall prognosis of CRS in the elderly remains poor. Treatments are primarily directed at addressing the sequelae of the underlying aetiology, which often involves the removal of fluid through diuretics or ultrafiltration. Careful considerations when managing elderly patients with CRS is essential due to the high prevalence of frailty and functional decline. As such, in these patients, early discussions around advance care planning should be prioritised. Full article

Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates obstructing these sinusoids. Both liver and spleen stiffness are significantly higher in myelofibrosis, correlating with the severity of bone marrow fibrosis. Spleen stiffness is also elevated in myelofibrosis and polycythemia Vera compared to essential thrombocythemia. MPNs are a leading cause of splanchnic vein thrombosis in the absence of cirrhosis or local malignancy, especially in the presence of the JAK2V617F mutation. This mutation promotes thrombosis through endothelial dysfunction and inflammation. It is found in endothelial cells, where it enhances leukocyte adhesion and upregulates thrombogenic and inflammatory genes. Hepatic sinusoidal microthromboses in MPNs may contribute to portal hypertension and liver dysfunction. MPN therapies can also affect liver function. While hepatocytolysis has been reported, agents such as Hydroxycarbamide and Ruxolitinib exhibit antifibrotic hepatic effects in experimental models. Overall, MPNs are linked to chronic inflammation, increased thrombotic risk—particularly splanchnic thrombosis—and atherogenesis. Full article

Systemic sclerosis (SSc) is an autoimmune fibrotic disorder affecting the skin and internal organs, categorized as either limited cutaneous SSc, where distal areas of skin are involved, or diffuse cutaneous SSc, where more extensive proximal skin involvement is seen. Vascular remodelling and internal organ involvement are frequent complications in both subsets. Multiple pathogenic mechanisms have been demonstrated, including production of disease-specific autoantibodies, endothelial cell damage at an early stage, infiltration of involved tissues by immune cells, as well as environmental factors triggering the onset such as solvents and viruses. Although not strongly familial, susceptibility to SSc is associated with multiple single nucleotide polymorphisms in immunoregulatory genes relevant to antigen presentation, T cell signalling and adaptive immunity, as well as innate immunity. In addition, several lines of evidence demonstrate abnormalities within the epithelial cell layer in SSc. Macroscopically, the SSc epidermis is pigmented, thickened and stiff and strongly promotes myofibroblasts in co-culture. Moreover, multiple activating factors and pathways have been implicated in the disease epidermis, including wound healing responses, induction of damage associated molecular patterns (DAMPS) and the release of pro-fibrotic growth factors and cytokines. Similar to SSc, data from studies of cutaneous wound healing indicate a major role for epidermal keratinocytes in regulating local fibroblast responses during repair of the wound defect. Since the epithelium is strongly exposed to environmental factors and richly populated with protective immune cells, it is possible that disease-initiating mechanisms in SSc involve dysregulated immunity and tissue repair within this cell layer. Treatments designed to restore epithelial homeostasis or else disrupt epithelial–fibroblast cross-talk could be of benefit in this severe and resistant disease. Accordingly, single cell analysis has confirmed an active signature in SSc keratinocytes, which was partially reversed following a period of JAK inhibitor therapy. Full article

Duplex-Doppler ultrasonography has become an essential tool in the diagnosis and management of kidney diseases, allowing clinicians to assess renal hemodynamics, detect vascular abnormalities, and monitor disease progression. Among the various Doppler-derived parameters, the renal resistive index (RRI) has gained particular attention both as a diagnostic tool and a prognostic marker in nephrology. Traditionally considered an indicator of parenchymal perfusion, recent evidence highlights its strong association with systemic hemodynamic factors, particularly arterial stiffness, positioning RRI as a valuable tool for evaluating patients with systemic vascular impairment, such as hypertension, diabetes mellitus, and atherosclerosis. RRI has been strongly linked to vascular damage, which in turn is influenced by inflammation and endothelial dysfunction, making it a reliable marker of cardiovascular damage and a potential predictor of cardiovascular risk. Furthermore, emerging studies suggest that RRI could serve as a dynamic parameter to monitor vascular changes induced by therapeutic interventions. This narrative review summarizes the classic and evolving applications of RRI, from its origin as a renal hemodynamic marker to its emerging role as a systemic vascular biomarker with diagnostic and prognostic significance in cardiovascular and metabolic diseases. Full article

Arterial stiffness indicates early atherosclerotic changes prevalent in children and adolescents with type 1 diabetes (T1D), even in those with a well–controlled disease and without additional cardiovascular risk factors. This study aimed to determine whether low–density lipoprotein (LDL) cholesterol and cytokine levels can indicate vascular stiffness in pediatric patients without conventional microangiopathic complications who are not undergoing lipid–lowering therapy. The total study group consisted of 59 pediatric patients divided into two subgroups based on their LDL cholesterol levels and matched for age, age at onset, and duration of diabetes. The investigation involved the precise measurement of several biomarkers including tumor necrosis factor (TNF–α), interleukin 35 (IL-35), interleukin 4 (IL-4), interleukin 10 (IL-10), interleukin 12 (IL-12), interleukin 18 (IL-18), vascular endothelial growth factor (VEGF), Soluble Vascular Cell Adhesion Molecule–1 (sVCAM–1), Intercellular Adhesion Molecule–1 (ICAM-1), Soluble Platelet Selectin (sP–Selectin), Advanced Glycation End Products (AGEs), and Receptors for Advanced Glycation End Products (sRAGE). Arterial stiffness was assessed by calculating pulsatility indices in the common carotid artery and the peripheral arteries in the upper and lower limbs. The comparative analysis indicated that, in the subgroup with LDL cholesterol levels below 100 mg/dL, in comparison to the subgroup with LDL above 100 mg/dL, there was a significant increase in pulsatility indices in elastic and large muscle arteries and notably higher levels of IL-35, IL-10, sVCAM–1, and ICAM-1. This study is the first to recommend the pulsatility index of elastic and large muscular arteries as an effective diagnostic tool for evaluating early atherosclerotic lesions in children and adolescents diagnosed with type 1 diabetes. Elevated LDL cholesterol levels may contribute to vascular stiffness through mechanisms related to a weakened inflammatory response, highlighting the complex interaction between lipid levels, inflammation, and vascular health in patients with type 1 diabetes. Full article

Background: Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vasculopathy, autoimmunity, and fibrosis. Due to its low prevalence and heterogeneous clinical presentation, early diagnosis remains challenging, often delaying appropriate treatment. The disease progresses from microvascular dysfunction, manifesting as Raynaud’s phenomenon, to systemic fibrosis affecting multiple organs, including the lungs, gastrointestinal tract, heart, and kidneys. There have been considerable advancements in understanding the pathophysiology of the disease during the last few years and this has already resulted in the improvement of the therapeutic approaches used to control organ-specific manifestations. However, the underlying cause of the disease still remains incompletely elucidated. Methods: Here, we summarize the current knowledge on the SSc pathogenesis. Results: The pathophysiology involves an interplay of chronic inflammation, impaired vascular function, and excessive extracellular matrix deposition, leading to progressive organ damage. Endothelial dysfunction in SSc is driven by immune-mediated injury, oxidative stress, and the imbalance of vasoconstrictors and vasodilators, leading to capillary loss and chronic hypoxia. Autoantibodies against endothelial cells or other toxic factors induce apoptosis and impair angiogenesis, further exacerbating vascular damage. Despite increased angiogenic factor levels, capillary repair mechanisms are defective, resulting in progressive ischemic damage. Dysregulated immune responses involving Th2 cytokines, B cells, and macrophages contribute to fibroblast activation and excessive collagen deposition. Transforming growth factor-beta (TGF-β) plays a central role in fibrotic progression, while fibroblasts resist apoptosis, perpetuating tissue scarring. The extracellular matrix in SSc is abnormally stiff, reinforcing fibroblast activation and creating a self-perpetuating fibrotic cycle. Conclusions: Advances in molecular and cellular understanding have facilitated targeted therapies, yet effective disease-modifying treatments remain limited. Future research should focus on precision medicine approaches, integrating biomarkers and novel therapeutics to improve patient outcomes. Full article

Background and objective: Menopause is a significant physiological milestone in a woman’s life, coinciding with increased cardiovascular disease (CVD) risk due to various health-related changes. This narrative review focuses on cardiovascular health-related alterations during menopause and their implications on vascular function. Methods: An electronic database search was performed, drawing from sources such as PubMed and Google Scholar. Publications were included if they addressed CVD risk in peri- and postmenopausal women, and examined the impact of hormonal changes, traditional risk factors (e.g., hypertension, hyperlipidemia, diabetes), or lifestyle factors (e.g., diet, physical activity) on CVD. Results: Estrogen deficiency is pivotal, leading to adverse effects such as endothelial dysfunction, increased arterial stiffness, and lipid profile deterioration. Characteristics of menopause, including the age at onset, type or stage of menopause, and severity of symptoms, further modulate CVD risk. Additionally, the impact of traditional risk factors is amplified during this period. Strategies for the prevention of CVD in menopausal women are critically assessed, with a focus on lifestyle modifications, dietary interventions, and physical activity. Conclusions: This narrative review describes the potential benefits and risks of hormone therapy, alongside lipid-lowering therapies. Emphasis is placed on individualized risk assessment and management, highlighting the need for regular cardiovascular screenings and proactive management of risk factors. Full article

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes. Full article

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated sinusoids are often linked to the liver stiffening that occurs through mechanotransduction-regulated processes. We performed a detailed characterization of polyacrylamide (PAA) hydrogels using atomic force microscopy (AFM), rheometry, scanning electron microscopy, and fluorescence microscopy to assess their potential as biomimetic substrates for LSECs. We additionally implemented AFM; quantitative fluorescence microscopy, including high-resolution structured illumination microscopy (HR-SIM); and an endocytosis assay to characterize the morphology and function of LSECs. Our results revealed significant local variations in hydrogel stiffness and differences in pore sizes. The primary LSECs cultured on these substrates had a range of stiffnesses and were analyzed with regard to their number of fenestrations, cytoskeletal organization, and endocytic function. To explore mechanotransduction in inflammatory liver disease, we investigated LSECs from a genetic model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes and examined their ability to restore their fenestrations on soft substrates. Our study demonstrates the beneficial effect of soft hydrogels on LSECs. Control cells exhibited a similar fenestrated morphology and function compared to cells cultured on plastic substrates. However, the pathological LSECs from the genetic model of systemic inflammation regained their fenestrations when cultured on soft hydrogels. This observation supports previous findings on the beneficial effects of soft substrates on LSEC fenestration status. Full article

Background and Aims: Hepatokines have a regulatory function in adipose tissue inflammation, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular diseases, and atherosclerosis. Our aim was to evaluate the profile of proinflammatory cytokines and hepatokines in patients with MASLD and carotid atherosclerosis (CA). Methods: A prospective and basic research study was conducted on patients with MASLD. Clinical data were collected from a detailed medical history. Liver stiffness was measured using transient elastography, and carotid Doppler ultrasound was performed. Levels of basic biochemical parameters, systemic inflammation markers (TNF-α, IL-6, IL-10, IL-18), and hepatokines (FGF21, ANGPTL4, fetuin-A) were determined. The results were analyzed with SPSS v22.0 software. Results: Sixty-seven patients with MASLD were included, 72.1% were women, and the mean patient age was 53.9 + 11.3 years. Atherosclerosis was found in 11 patients (16.2%), and carotid intima–media thickness (CIMT) was altered in the right carotid of 13 patients (19.1%), in the left carotid of 19 (27.9%), and bilaterally in 7 (10.3%). Greater age (p = 0.001) and high blood pressure (p = 0.028) were correlated with atherosclerosis. There were no differences in systemic inflammation markers, and the hepatokines FGF21 and fetuin-A tended to increase in the presence of CIMT and CA alterations, regardless of fibrosis. Conclusions: In our population, patients with MASLD had a 16.6% prevalence of CA, and the risk increased with age and a history of high blood pressure. FGF21 tended to increase in patients with MASLD + atherosclerosis, and fetuin-A was correlated with CIMT alterations, suggesting that the combination of these markers could guide us to suspect early endothelial alterations in patients with MASLD. Full article

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

Angiogenesis, the process of vessel formation from pre-existing ones, is modulated by the local stiffness of the extracelluar matrix. We have previously shown that Notch signaling, a key pathway in angiogenesis, responds to substrate stiffness in endothelial cells. In the current work, we investigate the contribution of Notch signaling in angiogenesis-related in vitro assays by using VEGF and Notch inhibitors as perturbations. In addition, we investigate Notch signaling in relation to the stiffness of the respective endothelial microenvironment. While the tube formation assay on Matrigel is clearly influenced by substrate stiffness, Notch signaling seems to play no major role in this context. In contrast, spheroid sprouting is influenced by stiffness as well as Notch signaling; with decreasing stiffness, both sprouting and Notch signaling are increased. This finding adds a functional aspect to the mechanosensitivity of Notch signaling. Full article

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) can damage the endothelium and increase arterial stiffness, potentially leading to adverse cardiovascular events. In parallel, systemic inflammation in COVID-19 also impacts endothelial function. Angiotensin-converting enzyme 2 (ACE2) promotes vasodilation and anti-inflammatory effects, but also facilitates SARS-CoV-2 entry into human cells. Thus, concerns have been raised about the use of RAAS inhibitors (RAASi) in COVID-19 patients due to potential ACE2 upregulation. However, the clinical significance of increased plasma ACE2 (sACE2) in RAASi-treated COVID-19 patients remains unclear. Methods: This prospective, single-centre study evaluated RAASi, sACE2, and vascular function in acutely ill patients with COVID-19 in comparison with acutely ill patients without COVID-19. Adult emergency department patients with confirmed or suspected COVID-19 were enrolled and underwent pulse wave velocity, ankle brachial index, and sACE2 measurements. Results: In the 152 included patients (50% female, median age 62 years, 68% COVID-19 positive), the sACE2 values were slightly higher in the COVID-19 (0.485 [0.364–1.329]) than in the non-COVID-19 subgroup (0.458 [0.356–1.138]; p = 0.70). No significant differences in sACE2 were observed between patients with and without RAASi, regardless of COVID-19 status. Pulse wave velocity values differed significantly between groups (p = 0.015). Conclusions: In emergency department patients, sACE2 was upregulated in COVID-19 patients, probably due to oxidative stress and inflammation. RAASi did not increase sACE2, but may have protective effects against inflammation. Elevated sACE2 appeared to have a beneficial effect on arterial stiffness in all patients. These findings support continued RAASi therapy in COVID-19 patients to protect against chronic inflammation and apoptosis. Full article

Hypertension is a clinical condition associated with structural alterations in small, medium, and large arteries, also affecting target organs due to the mechanical effects of high blood pressure and shear stress. However, these vascular changes are also influenced by various inflammatory and neurohumoral mediators originating from the endothelium, the renin-angiotensin-aldosterone system, the neuroadrenergic system, and the perivascular fat. Specifically, chronic hypertension leads to vascular stretching, which triggers complex signaling pathways that promote vascular remodeling. The endothelium plays a crucial role in this process, as its function is impaired in hypertensive patients, leading to reduced nitric oxide-mediated vasodilation, increased vascular tone, and a proinflammatory and prothrombotic state. Along with structural changes, hypertension also triggers dynamic alterations in arterial distensibility and arterial wall properties, leading to increased arterial stiffness, which is strongly linked to cardiovascular outcomes and associated disability, as well as subsequent rehabilitation needs. Several non-invasive and highly reproducible methods are currently used to assess arterial stiffness, one of which is the cardio-ankle vascular index (CAVI). This article examines the association between arterial stiffness and high blood pressure, with a particular focus on the results of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. This study analyzes the determinants of arterial stiffness in the general population, the different hypertensive phenotypes affecting diurnal and nocturnal blood pressure profiles, and the impact of blood pressure control through antihypertensive treatment on arterial stiffness. Full article