Venous Remodeling Research Articles

In degenerative mitral regurgitation a combined speckle tracking analysis predicts right ventricular to pulmonary circulation uncoupling

Abstract Background Global Longitudinal Strain (GLS) and left atrial (LA) strain evaluation by Speckle Tracking Echocardiography (STE) have emerged as prognostic index in patients affected by degenerative mitral regurgitation (DMR). In this setting, the coupling between right ventricular (RV) function and the pulmonary circulation (PC) has demonstrated to be associated with cardiovascular outcome. However, the prevalence of RV to PC uncoupling in patients undergoing surgery for DMR and its relationship with left ventricular (LV) and LA functioning has poorly been investigated. Aims To investigate the determinants of longitudinal LV systolic and LA function, and their association with RV-to-PC coupling in a cohort of patients with DMR undergoing mitral valve surgery. Methods 380 consecutive patients affected by DMR who underwent mitral surgery (repair or replacement) were retrospectively enrolled. LV longitudinal systolic function was studied with GLS and LA function was evaluated analyzing LA strain at peak relaxation (Global peak atrial longitudinal strain). RV-to PC coupling was studied with TAPSE/PAPS ratio considering a cut-off of 0,40 mm/mmHg and correlated with LV and LA strain. Speckle tracking echocardiography was performed offline and all patients were in sinus rhythm. Results A total of 380 eligible patients (mean age 55±14 y, 66% male) who were admitted for mitral valve surgery at San Raffaele hospital (85% repair, 15% replacement) for hemodynamically significant DMR were retrospectively enrolled. Mean hospital stay was 11±8 days. At baseline, 70% of patients exhibited an increased left ventricular (LV) and left atrial (LA) size. However, a preserved LA reservoir function (mean GPALS 27.6±11) and LV longitudinal systolic function (mean GLS -20.8±3) was found. Interestingly, GLS emerged as a strong determinant of LA reservoir strain with a significant direct correlation observed between GLS and GPALS values (r = 0.4 CI 95% 0.3-0.6; p<0.01, Figure 1). Additionally, when correlated with TAPSE/PAPS ratio, patients with lower TAPSE/PAPS (<0.4 mm/mmHg) exhibited significantly lower values of Global Longitudinal Strain and LA reservoir strain (TAPSE/PAPS<0.4 mm/mmHg: GLS -17±7% and GPALS 22.7±11.3% vs TAPSE/PAPS≥0.4 mm/mmHg: GLS -22±8% and GPALS 27.8±12.7%; p<0.01, Figure 2). Conclusions In DMR, LV GLS represents a strong determinant of LA reservoir function with a strong association between echo-derived measures of LA mechanics and LV longitudinal systolic function. In this context, a combined speckle-tracking analysis of LV and LA dynamics was able to predict the right ventricular coupling with the pulmonary circulation, underlying that the deterioration of LV and LA dynamics favors pulmonary venous congestion and vascular remodeling, ultimately affecting the right ventricle. A multiparametric approach in this subset of patients appears of relevance to ease risk-stratification, potentially improving the long-term outcome.

Chronic hypoxia promotes pulmonary venous smooth muscle cell proliferation through the CaSR-TRPC6/ROCE pathway

The mechanism underlying chronic hypoxia (CH)-induced pulmonary venous remodeling remains unclear. Cell proliferation is key in vascular remodeling, and the calcium-sensing receptor (CaSR) protein contributes to CH-induced pulmonary venous smooth muscle cell (PVSMC) proliferation. In pulmonary arterial smooth muscle cells, CaSR and transient receptor potential canonical (TRPC) proteins interact, contributing to CH-induced cell proliferation via CaSR-TRPC1/6 signaling. We investigated whether a similar pathway exists in PVSMCs. Rat PVSMCs were isolated and subjected to CH. Cell proliferation was assessed by cell counting, CCK-8, and BrdU incorporation assays. Expression of CaSR and TRPC was analyzed by qPCR and western blotting, while interactions between CaSR and TRPC were detected by co-immunoprecipitation assay. Extracellular Ca2+ restoration was evaluated, to assess store- and receptor-operated Ca2+ entry (SOCE and ROCE, respectively). CH enhanced PVSMC numbers, viability, and DNA synthesis, and upregulated CaSR and TRPC6 expression. Further, CaSR and TRPC6 interacted with one another. CaSR inhibitors (NPS2143, NPS2390) reduced, whereas activators (spermine, R568) enhanced, CH-induced increases in PVSMC numbers, viability, DNA synthesis, and TRPC6 expression. CaSR knockdown using siRNA inhibited CH-induced TRPC6 upregulation and attenuated CH-induced increases in PVSMC numbers, viability, and DNA synthesis. TRPC6 knockdown had no significant effect on CH-induced CaSR upregulation, but significantly attenuated CH-induced increases in PVSMC number, viability, and DNA synthesis. CaSR knockdown reduced ROCE, but not SOCE, enhancement. Overall, CH promotes PVSMC proliferation through the CaSR-TRPC6/ROCE pathway.

Glycocalyx disruption, endothelial dysfunction and vascular remodeling as underlying mechanisms and treatment targets of chronic venous disease.

The glycocalyx is an essential structural and functional component of endothelial cells. Extensive hemodynamic changes cause endothelial glycocalyx disruption and vascular dysfunction, leading to multiple arterial and venous disorders. Chronic venous disease (CVD) is a common disorder of the lower extremities with major health and socio-economic implications, but complex pathophysiology. Genetic aberrations accentuated by environmental factors, behavioral tendencies, and hormonal disturbances promote venous reflux, valve incompetence, and venous blood stasis. Increased venous hydrostatic pressure and changes in shear-stress cause glycocalyx injury, endothelial dysfunction, secretion of adhesion molecules, leukocyte recruitment/activation, and release of cytokines, chemokines, and hypoxia-inducible factor, causing smooth muscle cell switch from contractile to synthetic proliferative phenotype, imbalance in matrix metalloproteinases (MMPs), degradation of collagen and elastin, and venous tissue remodeling, leading to venous dilation and varicose veins. In the advanced stages of CVD, leukocyte infiltration of the vein wall causes progressive inflammation, fibrosis, disruption of junctional proteins, accumulation of tissue metabolites and reactive oxygen and nitrogen species, and iron deposition, leading to skin changes and venous leg ulcer (VLU). CVD management includes compression stockings, venotonics, and surgical intervention. In addition to its antithrombotic and fibrinolytic properties, literature suggests sulodexide benefits in reducing inflammation, promoting VLU healing, improving endothelial function, exhibiting venotonic properties, and inhibiting MMP-9. Understanding the role of glycocalyx, endothelial dysfunction, and vascular remodeling should help delineate the underlying mechanisms and develop improved biomarkers and targeted therapy for CVD and VLU.

Abstract 4146316: Venous Remodeling and Occlusion Accompany Arterial Pathology in Patients with Chronic Limb Threatening Ischemia

Background: Chronic limb threatening ischemia (CLTI) is defined as the presence of peripheral artery disease (PAD) in combination with rest pain or tissue loss and represents advanced arterial occlusive disease. Little is known about associated venous pathology as prior pathologic reports were limited to evaluation of maximally diseased arterial lesions. Objectives: To characterize arterial and venous histopathology in patients with CLTI. Methods: Tissue containing peripheral arteries and veins from the femoropopliteal to distal tibial arteries was harvested from 10 patients who underwent amputation for CLTI (Fig 1). Vessels were sectioned at 0.5 cm intervals, and histopathologic features were catalogued across 535 arterial and 493 venous sections. Results: Consistent with PAD, atherosclerotic lesions were more prevalent in proximal than distal arteries; 81.8% (27/33) femoropopliteal sections compared to 26.6% (134/502) of tibial sections. Severe stenosis (>90%) was noted in 21.9% (117) of sections and was associated with atherosclerosis (pathological intimal thickening, fibroatheroma, fibrocalcific or fibro-osseous lesions) in 10.3% (12), luminal thrombi in 68.4% (80), or both in 21.4% (25) of arterial sections. In all patients and in 99.0% (488/493) of venous sections, irrespective of the degree of arterial luminal stenosis, adjacent large (≥1000µm) and small diameter veins revealed marked thickening of the vessel wall comprised of fibrosis and smooth muscle hyperplasia (Fig 2). While large veins retained luminal patency, small veins exhibited severe luminal stenosis or obliteration. Venous thrombosis was uncommon, occurring in 3.0% (15/493) of sections. Conclusions: Venous remodeling with stenosis and occlusion is highly prevalent and coincides with arterial disease pathology in patients with CLTI. This novel finding of previously underappreciated and severely altered venous pathology suggests a possible additional mechanism for limb ischemia in CLTI.

Abstract 4124084: Nitric Oxide Releasing Bionanomatrix Gel For Dialysis Arteriovenous Fistula Maturation

Introduction: About 600,000 patients in the US suffer from end-stage renal disease (ESRD); more than 75% of ESRD patients undergo dialysis. Vascular access dysfunction is a major cause of morbidity and hospitalization in dialysis patients. Arteriovenous fistulas (AVFs) are considered the gold standard of vascular access for dialysis. However, about 60% of AVFs fail to mature because of early venous neointimal development and poor vasodilation and vascular wall remodeling. Therefore, to promote AVF maturation, we propose the application of a nitric oxide (NO) releasing nanomatrix gel, or ‘NO gel’, on the created AVF. The NO gel is composed of peptide amphiphiles (PA), which contain a polylysine (KKKKK) group to form NO-donating residues. In this study, we test our hypothesis that the NO gel applied at AVF can promote AVF maturation by decreasing venous intimal hyperplasia, enhancing vasodilation and vascular outward remodeling in porcine model. Materials and Methods: PA containing with KKKKK was synthesized and charged with NO to produce NO gel. For in vivo studies, AVFs in porcine were created by connecting the jugular vein and carotid artery. The NO gel was applied perivascularly over the AVF anastomosis. And the pigs were sacrifice after 35 days. AVF hemodynamics were evaluated using MRI-based computed fluid dynamics analysis. Results: We found significant decrease in neointimal hyperplasia in porcine AVFs treated with NO gel compared to the control groups. Additionally, the percentage of open lumens was significantly higher in the NO gel-treated group. It is indicated that veins in NO treated group showed less fibrosis as an less type I collagen I produced in the NO treated group than control. Also, the NO gel significantly improved hemodynamics and vascular remodeling of porcine AVFs compared to the control. Conclusion: These results suggest that the NO gel plays a crucial role in AVF maturation by reducing intimal hyperplasia and stenosis following AVF creation in a pig model. When intimal hyperplasia is reduced and the vessel is dilated, less tensile force of blood flow is applied on the arterialized vein, directing the AVF to appropriate maturation.

Endothelial TGF-β Signaling Regulates Endothelial-Mesenchymal Transition During Arteriovenous Fistula Remodeling in Mice With Chronic Kidney Disease.

Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis in patients with end-stage kidney disease. Chronic kidney disease (CKD) is associated with endothelial injury, impaired AVF maturation, and reduced patency, as well as utilization. Because CKD is characterized by multiple pathophysiological processes that induce endothelial-to-mesenchymal transition (EndMT), we hypothesized that CKD promotes EndMT during venous remodeling and that disruption of endothelial TGF (transforming growth factor)-β signaling inhibits EndMT to prevent AVF failure even in the end-stage kidney disease environment. The mouse 5/6 nephrectomy and aortocaval fistula models were used. CKD was created via 5/6 nephrectomy, with controls of no (0/6) or partial (3/6) nephrectomy in C57BL/6J mice. AVF were created in mice with knockdown of TGF-βR1/R2 (TGF-β receptors type 1/2) in either smooth muscle cells or endothelial cells. AVF diameters and patency were measured and confirmed by serial ultrasound examination. AVF, both murine and human, were examined using Western blot, histology, and immunofluorescence. Human and mouse endothelial cells were used for in vitro experiments. CKD accelerates TGF-β activation and promotes EndMT that is associated with increased AVF wall thickness and reduced patency in mice. Inhibition of TGF-β signaling in both endothelial cells and smooth muscle cells decreased smooth muscle cell proliferation in the AVF wall, attenuated EndMT, and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. Human AVF also showed increased TGF-β signaling and EndMT. CKD promotes EndMT and reduces AVF patency. Inhibition of TGF-β signaling, especially disruption of endothelial cell-specific TGF-β signaling, attenuates EndMT and improves AVF patency in mouse AVF. Inhibition of EndMT may be a therapeutic approach of translational significance to improve AVF patency in human patients with CKD.

Innovative Approaches and Future Directions in the Management and Understanding of Varicose Veins: A Systematic Review.

Varicose veins, a prevalent condition that primarily affects the lower limbs, present significant hurdles in diagnosis and treatment due to their diverse causes. This study dives into the complex hormonal, environmental, and molecular elements that influence varicose vein genesis, emphasizing the need for precise diagnostic methods and changing therapy approaches to improve patient outcomes. It investigates the epidemiology and demographic distribution of varicose veins, delves into their pathophysiology, and assesses diagnostic methods such as duplex ultrasonography and the CEAP classification system. In addition, the study discusses novel therapies such as sclerotherapy and endovenous thermal ablation, as well as the effectiveness of existing diagnostic methods in detecting chronic venous illnesses. By investigating venous wall remodeling and inflammatory pathways, it gives a thorough knowledge of varicose vein formation. The study calls for future research that focuses on patient-centered methods, bioengineering advances, digital health applications, and genetic and molecular studies to improve the accuracy and effectiveness of vascular therapy. As a result, a multidisciplinary literature analysis was done, drawing on insights from vascular medicine, epidemiology, genetics, and pharmacology, to consolidate existing knowledge and identify possibilities to enhance varicose vein diagnosis, treatment, and patient care outcomes.

Ginger protects against vein graft remodeling by precisely modulating ferroptotic stress in vascular smooth muscle cell dedifferentiation

Vein graft failure (VGF) is associated with vein graft (VG) intimal hyperplasia, which is characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs). Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition, also known as dedifferentiation. There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation, exerting vasoprotective functions; however, the precise mechanisms have not been fully characterized. Therefore, we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation. Ginger significantly inhibited neointimal hyperplasia and promoted lumen opening in a 3-month VG, which was primarily achieved by reducing ferroptotic stress. Ferroptotic stress is a pro-ferroptotic state. Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type, forming neointima after vein transplantation. Ginger and its two main vasoprotective ingredients (6-gingerol and 6-shogaol) inhibit VSMC dedifferentiation by reducing ferroptotic stress. Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53 while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase (Alox5), both promoting ferroptosis. Furthermore, both ingredients co-target peroxisome proliferator-activated receptor gamma (PPARγ), decreasing PPARγ mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) expression. Nox1 promotes intracellular reactive oxygen species (ROS) production and directly induces VSMC dedifferentiation. In addition, Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production, indirectly leading to VSMC dedifferentiation. Ginger, a natural multi-targeted ferroptotic stress inhibitor, finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.

Heterogeneous gene expression during early arteriovenous fistula remodeling suggests that downregulation of metabolism predicts adaptive venous remodeling

Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a ‘normal’ AVF (nAVF) group and an ‘outliers’ (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.

Elevated Shear Stress Modulates Heterogenous Cellular Subpopulations to Induce Vascular Remodeling.

Rationale: Elevated shear stress (ESS) induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arteriovenous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with a single-cell resolution before. Objective: Using an invivo animal mode, single-cell RNA sequencing, and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling. Methods: AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote ESS. Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls. Findings: ESS promoted transcriptional homogeneity, and NSS promoted considerable heterogeneity. Specifically, ESS endothelial cells (ECs) showed a more homogeneous transcriptional response promoting angiogenesis and upregulating endothelial-to-mesenchymal transition inhibiting genes (Klf2). NSS ECs upregulated antiproliferation genes such as Cav1, Cst3, and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated, proinflammatory and thus proangiogenic myeloid phenotype, whereas NSS myeloid cells expressed the anti-inflammatory and antiangiogenetic marker Mrc1. Conclusion: ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.

Vicious Circle With Venous Hypertension, Irregular Flow, Pathological Venous Wall Remodeling, and Valve Destruction in Chronic Venous Disease: A Review.

Substantial advances occurred in phlebological practice in the last two decades. With the use of modern diagnostic equipment, the patients' venous hemodynamics can be examined in detail in everyday practice. Application of venous segments for arterial bypasses motivated studies on the effect of hemodynamic load on the venous wall. New animal models have been developed to study hemodynamic effects on the venous system. In vivo and in vitro studies revealed cellular phase transitions of venous endothelial, smooth muscle, and fibroblastic cells and changes in connective tissue composition, under hemodynamic load and at different locations of the chronically diseased venous system. This review is an attempt to integrate our knowledge from epidemiology, paleoanthropology and anthropology, clinical and experimental hemodynamic studies, histology, cell physiology, cell pathology, and molecular biology on the complex pathomechanism of this frequent disease. Our conclusion is that the disease is initiated by limited genetic adaptation of mankind not to bipedalism but to bipedalism in the unmoving standing or sitting position. In the course of the disease several pathologic vicious circles emerge, sustained venous hypertension inducing cellular phase transitions, chronic wall inflammation, apoptosis of cells, pathologic dilation, and valvular damage which, in turn, further aggravate the venous hypertension.

#2709 Genome wide association study regarding disturbed AVF patency

Abstract Background and Aims Veins are frequently exposed to arterial circulation, as coronary artery bypass grafts (CABG) and as a peripheral venous bypass to treat atherosclerotic disease, or in the case of arterio-venous fistulas (AVF) to provide a vascular access for hemodialysis. Therapeutic success is dependent on proficient venous remodeling after introduction in the arterial circulation to sustain the increased hemodynamic pressure. Frequently observed adverse outcomes after the aforementioned procedures include the stenosis or total occlusion of the vein, requiring surgical or interventional treatment or leading to bypass/ AVF failure. Hereditary factors associated with disturbed venous patency have been previously investigated in all three conditions. For example, distinct VEGF-A as well as TGF-beta polymorphisms have been identified to correlate with AVF failure. In the present analysis we aimed at investigating whether genetic polymorphisms associated with disturbed venous patency after AVF creation are similar to findings in CABG and peripheral bypass patients in a genome wide association study. Method The analyses were conducted in White Europeans (N= 425,406) in the UK Biobank using regenie software. This software employs a linear mixed model that accounts for the impact of population structure and individual relatedness. Out of approximately 805,000 variants, we selected 606,201 high-quality variants to construct a relatedness model for regenie. These selected variants were identified by a genotyping rate exceeding 80%, minor allele frequencies greater than 1%, and Hardy-Weinberg equilibrium p-values below 10^-8. We adjusted for age, sex, BMI, smoking, and history venous thromboembolism. We assessed the association of 9,757,417 imputed SNPs, each having a minimum allele count of 12 and a minimum info score of 0.3. Results In total, 768 patients underwent at least 1 surgery for AVF creation. Out of those, 341 (44.4%) had a recorded procedure or diagnosis associated with disturbed fistula patency. The controls included 6067 CABGs and 384 peripheral bypasses with 76 (1.3%) and 67 (17.4%) recorded events, respectively. We found no genome wide significant associations for the tested SNPs and patency-related AVF complications (Fig. 1). Additionally, we also found no genome wide significant associations after combining the phenotypes (Fig. 2). Conclusion Multiple studies have evaluated genetic associations and adverse clinical outcomes after AVF creation. Nevertheless, the generalizability of these findings might be limited at least partially due to small sample sizes. While the sample size of the present analysis is similar to previous research efforts and therefore also comparably low, the lack of consistency in results might be suggestive of the difficulties research in this field faces. Additionally, we found no indication that impaired venous patency after AVF creation is related to complications after coronary or peripheral bypass surgery regarding genetic patient profiles. However, whether this is due to differences in pathophysiology and related genetic predispositions or due to the limited sample size and incidence rates of the present study remains to be determined in follow-up investigations.

Mechanoresponsive ETS1 causes endothelial dysfunction and arterialization in varicose veins via NOTCH4/DLL4 signaling

Varicose veins are the most common venous disorder in humans and are characterized by hemodynamic instability due to valvular insufficiency and orthostatic lifestyle factors. It is unclear how changes in biomechanical signals cause aberrant remodeling of the vein wall. Our previous studies suggest that Notch signaling is implicated in varicose vein arterialization. In the arterial system, mechanoresponsive ETS1 is a transcriptional activator of the endothelial Notch, but its involvement in sensing disrupted venous flow and varicose vein formation has not been investigated. Here, we use human varicose veins and cultured human venous endothelial cells to show that disturbed venous shear stress activates ETS1-NOTCH4/DLL4 signaling. Notch components were highly expressed in the neointima, whereas ETS1 was upregulated in all histological layers of varicose veins. In vitro microfluidic flow-based studies demonstrate that even minute changes in venous flow patterns enhance ETS1-NOTCH4/DLL4 signaling. Uniform venous shear stress, albeit an inherently low-flow system, does not induce ETS1 and Notch proteins. ETS1 activation under altered flow was mediated primarily by MEK1/2 and, to a lesser extent, by MEK5 but was independent of p38 MAP kinase. Endothelial cell-specific ETS1 knockdown prevented disturbed flow-induced NOTCH4/DLL4 expression. TK216, an inhibitor of ETS-family, prevented the acquisition of arterial molecular identity and loss of endothelial integrity in cells exposed to the ensuing altered shear stress. We conclude that ETS1 senses blood flow disturbances and may promote venous remodeling by inducing endothelial dysfunction. Targeting ETS1 rather than downstream Notch proteins could be an effective and safe strategy to develop varicose vein therapies.

Abstract 1130: Tenascin-C In Arteriovenous Fistula Failure: Unraveling Venous Remodeling Dynamics

Background: AVF are the preferred vascular access for hemodialysis, with superior patency and lower infection rates than grafts or catheters. Nevertheless, AVF patency is reduced by both early thrombosis and NIH, culminating in diminished utilization due to one-year patency rates as low as 40-50%. Tenascin-C (TnC), an ECM glycoprotein with limited adult expression, is transiently present at sites of tissue injury and inflammation. TnC has been implicated in playing a role in the development of NIH. Hypothesis: Sustained TnC expression contributes to NIH, potentially leading to AVF failure. Methods: Female and male wild-type C57Bl/6 mice, aged 9-11 weeks, had sham surgery or AVF creation by puncturing the infrarenal aorta into the inferior vena cava (IVC) with a 25-gauge needle. Doppler ultrasound confirmed AVF presence. Tissue samples were collected for IF, WB, and qPCR. Human matched vein and AVF tissue were obtained from patients undergoing planned two-stage AVF creation surgeries and analyzed with IF. In vitro analysis of human dermal microvascular endothelial cells (HDMEC) was performed to investigate the role of TnC in thrombomodulin expression. Results: TnC expression significantly increased in the AVF by day 7, returning to baseline by day 21 and reaching negligible levels by day 42. The spatial and temporal regulation of TnC expression post-AVF creation correlated with ECM remodeling and inversely with thrombomodulin. Both mice and human studies demonstrated differential regulation of TnC and thrombomodulin in patent and occluded AVF. In HDMEC, TnC knockdown suppressed NF-kB expression and increased thrombomodulin expression, while exogenous TnC had the opposite effect. Conclusion: TnC plays a pivotal role in driving pathological inflammation, with its expression being both temporally and spatially regulated during venous remodeling post-AVF creation. Persistent TnC expression is noted in occluded mouse and human AVF, leading to decreased thrombomodulin expression and heightened thrombogenicity. Sustained TnC expression regulates the shift from physiological to pathological venous remodeling, underscoring the crucial role of the immune response in this process and highlighting potential translational therapeutic strategies.

Experimental multiparametric magnetic resonance imaging characterization of iliocaval venous thrombosis pathological changes

ObjectiveIliocaval thrombotic obstruction is a challenging condition, especially because thrombus age and corresponding pathological remodeling at presentation are unknown, which directly impacts management. Our aim was to assess the ability of magnetic resonance imaging (MRI) in determining age thresholds of experimentally created inferior vena cava (IVC) thrombosis in pigs. MethodsWe used a previously described swine model of IVC thrombosis. The animals underwent MRI at baseline, immediately after thrombosis creation, and after a follow-up period extending from 2 to 28 days. Thirteen pigs were divided into three groups according to disease chronicity: acute group (AG; n = 5), subacute group (SAG; n = 4), and chronic group (CG; n = 4), with a mean thrombosis age of 6.4 ± 2.5 days, 15.7 ± 2.8 days, and 28 ± 5.7 days, respectively. A T1-weighted volumetric interpolated breath-hold examination sequence was used to anatomically delineate IVC thrombus as a region of interest. Three other MRI sequences were used to assess the thrombus signal. ResultsThe Kruskal-Wallis test showed a statistically significant difference in T1 relaxation times after contrast injection (P = .026) between the three groups of chronicity. The AG (360.2 ± 102.5 ms) was significantly different from the CG (336.7 ± 55.2 ms; P = .003), and the SAG (354.1 ± 89.7 ms) was significantly different from the AG (P = .027). There was a statistically significant difference in native T2 relaxation times (P = .038) between the three groups. The AG (160 ± 86.7 ms) was significantly different from the SAG (142.3 ± 55.4 ms; P = .027), and the SAG was significantly different from the CG (178.4 ± 11.7 ms; P = .004). ConclusionsThis study highlighted MRI characteristics in a swine model that might have the potential to significantly differentiate subacute and chronic stages from an acute stage of deep vein thrombosis in humans. Further clinical studies in humans are warranted. Clinical RelevanceIn addition to providing a better understanding of venous thrombosis remodeling over time, magnetic resonance imaging has the potential to be a tool that could allow us to characterize the composition of venous thrombus over an interval, allowing for a refined analysis of the local evolution of venous thrombosis. We propose a noninvasive and innovative method to characterize different thresholds of chronicity with magnetic resonance imaging features of central deep vein thrombosis of the inferior vena cava experimentally obtained using a totally endovascular in vivo swine model, mimicking human pathophysiology. Being able to determine these features noninvasively is critical for vascular specialists when it comes to choosing between fibrinolytic therapy, percutaneous thrombectomy, or surgical management.

A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function.

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs.

One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. There are many etiological environmental factors influencing the development of chronic venous insufficiency (CVI), although genetic factors and family history of the disease play a key role. All these factors induce changes in the hemodynamic in the venous system of the lower limbs leading to blood stasis, hypoxia, inflammation, oxidative stress, proteolytic activity of matrix metalloproteinases (MMPs), changes in microcirculation and, consequently, the remodeling of the venous wall. The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. Particular emphasis has been placed on describing the role of inflammation and oxidative stress and the involvement of extracellular hemoglobin as pathogenetic factors of VV. Additionally, active substances used in the treatment of VV were discussed.

The Effect of Standardized Doses of Hesperidin and Diosmin on Venous Wall Remodeling in Patients with Primary Varicose Veins: a Prospective Controlled Study “STANDARD”

The Effect of Standardized Doses of Hesperidin and Diosmin on Venous Wall Remodeling in Patients with Primary Varicose Veins: a Prospective Controlled Study “STANDARD”

Combined Use of Copernic RC Venous Remodeling Balloon and Aspiration Thrombectomy for Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis is a potentially fatal condition. The current first line of treatment for sinus thrombosis is anticoagulation. Endovascular treatment is an alternative for patients whose symptoms progress despite adequate medical management. Mechanical thrombectomy is required in the setting of a large clot burden. Unfortunately, the conventional technique of intraarterial thrombectomy with the use of a stent retriever and/or aspiration is not very effective in sinus thrombosis because of a larger clot burden compared to an intracranial artery. Herein we describe our endovascular approach of mechanical thrombectomy in sinus thrombosis using Copernic 8 × 80 RC (Rene Chapot) balloon and aspiration catheter.

Left atrial dynamics and the pulmonary circulatory-right ventricular uncoupling in patients with severe degenerative mitral regurgitation

Abstract Funding Acknowledgements Type of funding sources: None. Background The uncoupling of right ventricular (RV) function to pulmonary circulation (Pc) represents a prognostic index in patients affected by degenerative mitral regurgitation (DMR) undergoing surgical or percutaneous repair. In this context, the deterioration of Left Atrial (LA) dynamics favors the development of pulmonary venous congestion and vascular remodeling, triggering pulmonary hypertension (PH) and right ventricular (RV) dysfunction. However, the relationship between LA function and RV-to-Pc coupling is not well defined in this population. Purpose The aim of the study was to investigate the association between RV-to-Pc uncoupling, assessed by the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PAPS), and LA dynamics, evaluated with Speckle Tracking Echocardiography (STE), in patients with DMR. Methods 351 consecutive patients with hemodynamically-significant DMR who were evaluated for cardiac surgery at San Raffaele Hospital and underwent a complete transthoracic and transesophageal echocardiography were retrospectively enrolled (mean age 59±14 years, 65% males). Patients were then stratified in two groups according to TAPSE/PAPS ratio (group I: TAPSE/PAPS >0.4 mm/mmHg; group II: TAPSE/PAPS ≤0.4 mm/mmHg). LA function was evaluated analyzing LA strain at peak relaxation (Global peak atrial longitudinal strain) and STE analysis was performed offline. All the patients enrolled were in sinus rhythm. Results At baseline, patients exhibited normal LV dimensions and function (EDVi 70±20 ml/m2, LVEF 63±6%), increased LA size (48±20 ml/m2) and a mean GPALS of 26±13%. Additionally, a preserved RV function and coupling with PC was found in the population in study (average TAPSE/PASP at admission: 0.84±0.2 mm/mmHg), with only 10% of the cohort exhibiting a reduced TAPSE/PAPS ratio. When stratified according to RV-to-PC coupling, patients with higher TAPSE/PAPS (>0.4 mm/mmHg) exhibited significantly higher values of LA reservoir strain (group I: GPALS 27.8±12.7% vs group II GPALS 22.7±11.3%; p = 0.04) (Figure 1, 2). Additionally, a direct correlation between LA-Strain values and TAPSE/PAPS ratio was noticed (r=0.3, CI 95% 0.21–0.5; p<0.001). Conclusions In DMR, there is a strong association between echo-derived measures of LA mechanics and RV to Pc uncoupling, with higher values of LA strain correlating with a better RV functioning and coupling. These results, although preliminary, suggest the importance of a multiparametric approach in the risk-stratification of these patients, potentially improving the long-term outcome.