Aortocaval Fistula Research Articles

TIPS, a Trick for Transcaval TEVAR Access.

We described an alternative access for thoracic endovascular aortic repair (TEVAR) deployment using a transjugular intrahepatic portosystemic shunt (TIPS) needle for gaining transcaval access to the abdominal aorta. A 63-year-old man presented with a penetrating atherosclerotic ulcer in the descending aorta. Traditional transfemoral and transaxillary access were not possible. A transcaval access was established using a TIPS needle to puncture from the caval vein to the aorta. Next, the access was gradually upsized until a 22 french large-bore transcaval access was achieved. Afterwards the thoracic endograft was positioned and deployed accustomed. The infrarenal aortocaval fistula was closed with a covered stent. When classic TEVAR access is not possible, transcaval access is a valuable and minimally invasive alternative access. We prefer the use of a TIPS needle for gaining access and use a covered stent for closing the aortic access site when possible instead of using electrified wires nor a transseptal occluder device. Preoperative planning remains key. We discribe a transcaval access with a TIPS needle and closing of the aortocaval fistula with a covered stent. We are one of fiew reports of transcaval puncturing instead of using an electrified wire and the first using a TIPS needle for gaining transcaval access. We hope this case and our comments help other surgeons, radiologists and patients when they are in need of a transcaval access and contribute to a successful procedure.

Abstract 4138449: High Output Heart Failure from an Aortocaval Fistula

Introduction: High output heart failure (HOHF) due to a post-traumatic aortocaval fistula is a rare entity. This case seeks to explore the presentation as well as complexities of management of these patients. Case Presentation: A 50-year-old male with a prior right abdominal stab wound requiring exploratory laparotomy 20 years ago presented with worsening dyspnea on exertion and palpitations. Physical examination was remarkable for jugular venous distention, lower extremity edema, and a pulsatile mass in the right abdomen with an audible bruit. A 12-lead ECG showed rapid atrial flutter. A transthoracic echocardiogram (TTE) showed a reduced left ventricular ejection fraction (LVEF) of 30-35%, severely dilated atria and inferior vena cava (IVC) with high velocity flow. Abdominal computed tomography venogram showed dilation of the IVC up to 8cm and an aortocaval fistula at the level of the right renal vessels, resulting in an atrophic right kidney. Cardiac catheterization was notable for a cardiac output (CO) of 12L/min, cardiac index (CI) of 7L/min/m2 and reduced systemic vascular resistance (SVR). He was managed with beta blockers and diuretics, followed by TEE-guided cardioversion for atrial flutter to restore sinus rhythm. Vascular surgery performed a successful, first of its kind endovascular repair of the abdominal aorta with stenting of the right common iliac artery and placement of a 20mm Amplatzer Septal Occluder device in the right renal artery. He tolerated the procedure well, and post-operative TTE showed a recovered LVEF of 55-60% and CO of 6L/min. Discussion: HOHF is defined by a CO more than 8L/min or CI more than 4L/min/m2 along with clinical symptoms. Decreased SVR leads to sympathetic activation and stimulation of the renin-angiotensin-aldosterone system, leading to fluid retention, cardiac remodeling, and exacerbation of symptoms. Challenges present in the management of HOHF and the use of vasodilatory agents should be avoided, as they can exacerbate the problem. In our case, limitations were also faced in the use of many traditional HF therapies due to renal dysfunction as a result of the fistula. Therefore, repair was the only viable long-term solution. Conclusion: This case displays an uncommon etiology of HOHF, emphasizing the need for meticulous evaluation to ensure proper management. Early detection of aortocaval fistulas is crucial to prevent worsening cardiac dysfunction, with symptoms resolving rapidly post-repair.

Endovascular Repair of Primary Aortocaval Fistula at the Caval Confluence in a Ruptured Abdominal Aortic Aneurysm.

Background: Primary aortocaval fistulas (ACF) are a rare complication of abdominal aortic aneurysm (AAA), for which treatment options encompass both endovascular and open surgical intervention. Purpose: To report a rare presentation of primary aortocaval fistula. Research Design: Case Report. Study Sample: Single Patient Case. Data Collection and/or Analysis: Single case report. Results: We present a 54-year-old male with a ruptured AAA and associated ACF uniquely located near the caval confluence which was managed through primary endovascular exclusion. Notably, we report significant migration of our graft upon deployment, due to high flow through the ACF. Following a literature review on ACFs, we remark on the anatomic challenges regarding management of an ACF. Conclusions: Awareness of the clinical signs and symptoms remains imperative in proper ACF management given its high mortality.

Contrast-enhanced CT: aortocaval fistula secondary to a ruptured abdominal aortic aneurysm

Contrast-enhanced CT: aortocaval fistula secondary to a ruptured abdominal aortic aneurysm

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

Arteriovenous fistulae (AVFs) 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. AVFs 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.

O07 RENAL DENERVATION IMPROVES RIGHT VENTRICULAR FUNCTION, RESTORES MYOCARDIAL NOREPINEPHRINE LEVELS AND REVERSES VENTRICULAR SPECIFICITY OF SELECTED MARKERS IN HYPERTENSIVE RATS WITH HEART FAILURE INDUCED BY VOLUME OVERLOAD

Background and objective: Despite the known anti-hypertensive effect of renal denervation (RDN), its influence on the cardiac function, particularly of the right ventricle (RV) and the cardiac sympathetic nervous system in heart failure (HF) is poorly understood. This study aimed to investigate the effect of RDN on RV function, myocardial norepinephrine (NE), and left versus right ventricular (LV/RV) dominance of HF markers in HF induced by aorto-caval fistula (ACF). Methods: ACF was created in hypertensive Ren-2 transgenic rats. RDN was performed by phenol application. Cardiac function was measured by echocardiography and pressure-volume analysis. NE levels were measured using an ELISA kit, protein expression was assessed by western blotting, gene expression by TaqMan PCR assay, and ROS by Amplex Red assay. Results: RDN in ACF rats decreased RV hypertrophy and dilatation, decreased RV end-systolic pressure and end-diastolic pressure, improved RV function (Ees +45%, FAC +20%), decreased HF gene markers Nppa, Tgm2, Myh7/6 ratio, and increased SOD2 protein expression. RDN decreased plasmatic NE levels, increased NE in RV, and decreased monoamine oxidase (MAO-A) in RV. NE levels and SOD2 were more dominant in RV than LV in control (sham/intact) rats and ACF changed their specificity towards RV dominance, while RDN had no effect in these parameters in ACF on ventricular specificity. In sham/intact rats dominant for LV were hemodynamic parameters Ees, EDPVR, and molecular markers Mao-a, ROS production by MAO-A, Nppa, Myh7, Myh7/6 ratio, Tgm2, Uchl1, and Beta1/Chrm2 ratio. ACF changed the dominance of these selected markers from LV to RV. Interestingly, RDN reversed dominance back towards LV in gene markers Mao-a, Nppa, Myh7, Tgm2, Uchl1, and Beta1/Chrm2 ratio. Conclusions: RDN decreased RV ESP and EDP, improved RV systolic function, restored NE levels, decreased RV gene expression of selected HF markers, and reversed their RV/LV dominance, probably by reduction of central sympathetic nerve drive and alternations of the cardiac sympathetic nervous system.

Aorto caval fistulas.

The purpose of this paper is to examine and assess the outcomes following open repair in 39 patients who experienced aorto-caval fistula (ACF) resulting from the spontaneous rupture of an abdominal aortic aneurysm (AAA). We reviewed the clinical records of all patients surgically treated with open repair for ACF at the Clinic for Vascular and Endovascular Surgery of the Serbian Clinical Center in Belgrade, Serbia, from January 2012 to February 2023. All of the patients in this series were consecutive and had aorto-caval fistula from AAA. No patients were excluded from the procedure due to the life-threatening nature of the state. A follow-up assessment was performed during the follow-up examination or by telephone interview with the patient or a family member. All patients were male, with mean age 67.4±8.3 years (range: 52-83 years). The 30-day mortality rate in our cohort was 35.9%, with three (7.7%) intraoperative deaths, and 11 deaths in the postoperative period (28.2%). A total of 25 patients out of 39 (64.1%) in the original cohort have survived the surgery and the postoperative period and were followed-up for a total of 67.1 person-years. The mean follow-up was 3.7±2.2 years (range 0.25-8.4 years). Two patients (8.0%) died during the follow-up, 16 patients (64.0%) survived, and seven (28.0%) were lost to follow-up. The long-term mortality rate in the cohort that survived the postoperative period was 3.0/100 person-years. ACF caused by spontaneous AAA rupture into the inferior caval vein or iliac veins is a relatively rare, life-threatening condition which requires prompt treatment. An exact preoperative diagnosis is essential for perioperative strategy. As the comparison of our results with the results from contemporary literature indicates, wherever possible endovascular repair should be considered since it results might be superior to open repair.

P164 SOLUBLE GUANYLATE CYCLASE STIMULATORS: AN EMERGING OPTION IN THE TREATMENT OF PRESSURE AND VOLUME OVERLOAD INDUCED CHRONIC HEART FAILURE

Pressure and volume overload-induced chronic heart failure (HF) is associated with characteristic cardiac remodeling and ventricular myocardial proteomic alterations, that can lead to the formation of a substrate for arrhythmias. Antiarrhythmic drug therapy is still suboptimal and current therapies are not efficacious enough. The purpose of the current study was therefore to examine the efficiency of nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) stimulator. We used as an experimental model male hypertensive Ren-2 transgenic rats (TGR) (n = 16), normotensive Hannover Sprague–Dawley rats (HSD, n = 17), and a volume-overload HF rat model induced by creating the aortocaval fistula (ACF) in rats of both strains (n = 27). Rats were after the induction of ACF treated by sGC stimulator BAY41-8543 (3 mg/kg/day for 30 weeks) alone or combined with angiotensin-converting enzyme inhibitor (ACEi) Trandolapril (0.25 mg/kg/day for 30 weeks). The age of the animals at the end of the experiment was 40 weeks. Left ventricle tissue and plasma samples were used for further analyses. Blood pressure (BP) was measured by telemetry. Combined treatment with sGC stimulator and ACEi was the most potent in lowering BP. Moreover, supplementation by sGC stimulator alone significantly decreased mortality and increased levels of the antioxidant enzyme superoxide dismutase 1, matrix metalloproteinase 2, total and phosphorylated connexin 43 as well as protein kinase C epsilon, implicated in remodeling of extracellular matrix and intercellular communication, in the left ventricle of TGR rats. Application of the sGC stimulator also slightly normalized elevated collagen deposition and hydroxyproline content in the left ventricular tissue of TGR rats. Unfortunately, we did not observe any effect of the sGC stimulator in the TGR ACF group. These results support the hypothesis that sGC stimulators might represent a class of drugs suitable for the prevention and treatment of related disorders in HF. This work was supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104. Supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104.

P163 EMPAGLIFLOZIN AND ITS CARDIOPROTECTIVE EFFECTS IN THE HEART DURING VOLUME OVERLOAD IN AN EXPERIMENTAL MODEL INDUCED BY AORTOCAVAL FISTULA

Mitral regurgitation causes volume overload of the heart, and due to the deregulation of extracellular matrix proteins, the electrical communication between cardiomyocytes provided by connexin channels is disturbed. The aim of this study was to investigate the effect of cardiac volume overload (VO) on its functional parameters, structural remodeling, and connexin43 (Cx43), a protein ensuring electrical synchronization of the heart, and the cardioprotective effect of empagliflozin. Cardiac VO was induced by surgical aortocaval fistula (ACF) in adult, 6-month-old male Wistar rats. Mitral regurgitation and VO developed within four weeks. Subsequently, empagliflozin was administered daily for five weeks at a dose of 10 mg/kg of body weight. Echocardiographic examination showed increased cardiac output and increased Vmax of the aortic valve, decreased ejection fraction and fractional shortening due to ACF-VO. Echocardiographic parameters showed an increase in the diameter of the left ventricle in both systole and diastole, as well as an increase in the volume of the left ventricle at the end of systole and diastole. Empagliflozin normalized the negative parameters in the ACF-VO group. Myocardial protein Cx43 levels were reduced by ACF-VO but normalized by empagliflozin treatment. In addition, empagliflozin suppressed the ACF-VO-induced increase in interstitial collagen detected by van Gieson staining. These findings were consistent with increased protein expression of MMP-2, which is involved in structural remodeling of the extracellular matrix, and was normalized by empagliflozin. Protein kinase C epsilon levels associated with Cx43 and extracellular matrix modulation were reduced by ACF-VO and normalized by empagliflozin. However, protein levels of pro-apoptotic and pro-hypertrophic protein kinase C delta were increased by ACF-VO and normalized by empagliflozin. Protein expression of transforming growth factor beta as well as fibroblast growth factor 21 was increased by ACF-VO and normalized by empagliflozin. The results indicate a cardioprotective effect of empagliflozin due to suppression of myocardial structural remodeling and preservation of Cx43 in an experimental model simulating volume overload. The research was supported by grants APVV-21-0410,VEGA-2/0006/23,VEGA-2/0133/24,VEGA-2/0002/20

Right-to-left shunt due to iatrogenic atrial septal defect manifested by aorto-caval fistula: a case report

BackgroundAn aorto-caval fistula is a rare but critical complication of abdominal aortic aneurysm (AAA) rupture, leading to high-output heart failure and increased venous pressure. The anesthetic management of such cases, particularly when complicated by an intraoperative right-to-left shunt, is seldom reported.Case presentationA 71-year-old man with a history of atrial fibrillation and catheter ablation presented with heart failure and abdominal pain, leading to cardiac arrest. Imaging revealed an AAA rupture into the inferior vena cava. During emergency surgery, severe venous bleeding was managed using intra-aortic balloon occlusion (IABO). Transesophageal echocardiography (TEE) identified a right-to-left shunt due to an iatrogenic atrial septal defect.ConclusionEarly TEE recognition and timely IABO intervention were crucial in managing this complex case, underscoring the importance of these techniques in similar emergency scenarios.

Abstract Tu057: Renal denervation enhances right ventricular function, reduces myocardial damage, and restores myocardial sympathetic signaling in rats with heart failure induced by volume overload

Introduction: Heart failure (HF) is associated with chronically increased sympathetic nervous activity with depleted norepinephrine (NE) in the myocardium. Despite the known anti-hypertensive effect of renal denervation (RDN), its influence on the function of the right ventricle (RV) and the cardiac sympathetic nervous system in HF is not well comprehended. Hypothesis: RDN improves RV function by reducing central sympathetic drive and changes of a sympathetic nervous branch in the heart. Aims: To investigate the effect of RDN on RV function, HF markers, myocardial NE, and its metabolism in RV in HF induced by aorto-caval fistula (ACF). Methods: HF was induced by ACF in Ren-2 transgenic rats (TGR). One week later, the RDN was performed by phenol application. Two weeks after RDN, RV function was measured by pressure-volume analysis and RV tissue was collected. Echocardiography was done once a week, during the entire experiment. NE levels were measured using an ELISA kit, protein expression was assessed by western blotting, gene expression by TaqMan PCR gene expression assay, and ROS by oxidation of Amplex Red assay. Results: The ACF increased RV weight, RV dimensions (RVD1, RVD2, RVD3), end-systolic (ESP) and end-diastolic pressure (EDP), reduced RV systolic function (end-systolic elastance - Ees, fractional area change - FAC) and ventricular-arterial coupling (Ees/Ea ratio), increased gene expression of HF markers collagen I/III ratio, natriuretic peptide A (Nppa), myosine heavy chain 7/6 (Myh7/6) ratio, transglutaminase 2 (Tgm2), and decreased superoxide dismutase 2 (SOD2) protein expression. ACF increased plasmatic NE levels, depleted NE in RV, decreased tyrosine hydroxylase protein expression in RV, and increased gene, protein expression, and activity of monoamine oxidase A (MAO-A). RDN decreased RV hypertrophy and dilatation (RVD1, RVD2, RVD3), decreased RV ESP (-7 mmHg, p=0.004) and EDP (-2.2 mmHg, p=0.003), improved RV function (Ees +45%, p=0.03, FAC +20%, p=0.005, Ees/Ea ratio +46%, p=0.02), decreased HF markers collagen I/III ratio, Nppa, Tgm2, Myh7/6 ratio, and increased SOD2 protein expression. RDN decreased plasmatic NE levels, increased NE in RV (+32%, p=0.03), and decreased MAO-A in RV. Conclusions: RDN decreased RV ESP and EDP, improved RV systolic function, restored NE levels, and decreased RV gene expression of selected HF markers, probably by reduction of central sympathetic nerve drive and alterations of the cardiac sympathetic nervous system.

Abstract Mo031: Tissue deficiency and altered eicosanoids levels in rodent and human heart failure.

Introduction: The role of eicosanoids, especially epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid with cardio-renal activity, in heart failure (HF) remains unclear. Hypothesis: Altered eicosanoids turnover, both in rodent and human heart failure, is a part of the pathophysiology of HF and contributes to poor prognosis. Methods: We measured active EETs and their biologically inactive metabolites, dihydroxyeicosatrienoic acids (DHETs) in the left ventricle (LV) and renal tissue obtained from a rodent heart failure model induced by aortocaval fistula (ACF). We measured protein expression of CYP2C23 and CYP2J3 in the kidney cortex and LV tissue by Western blot analysis to evaluate EETs production and mRNA expression of soluble epoxide hydrolase (sEH), the enzyme responsible for the degradation of EETs to DHETs. In the translational part, firstly, we enrolled 50 patients with HF to measure plasma 14,15-epoxyeicosatrienoic acid (14,15-EET) and 14,15-dihydroxyicosatrienoic acid (14,15-DHET) levels using commercial ELISA kits and compared them with 25 age- and sex-matched controls. Secondly, 11 consecutive patients with HFrEF indicated to cardiac resynchronization therapy (CRT) were enrolled to measure plasmatic 14,15-EET and 14,15-DHET levels in venous, arterial, and coronary sinus (CS) blood samples and correlate them with N-terminal pro-B-type natriuretic peptide (NT-proBNP) from the same compartments. Results: ACF rats exhibited tissue deficiency of EETs in the LV and kidney compared to controls, probably mainly caused by increased EETs degradation by sEH (unchanged expressions of CYP2C23 and CYP2J3, increased mRNA of sEH and EETs/DHETs ratio). In humans, both of the measured eicosanoids were significantly higher in the HF group: 14,15-EET (91.3 ±25.7 vs. 64.95 ±35.4 ng/ml) and 14,15-DHET (10.58 ±2.06 vs. 9.07 ±1.60 ng/ml), p for both < 0.001. HF patients with 14,15-EET levels less than 60 ng/ml had worse short term mortality compared to those above. In CS, NT-proBNP levels negatively correlated with plasmatic 14,15-EET levels (r = -0.63, p = 0.03) and positively with the DHET/EET ratio (r = 0.73, p = 0.02). Plasmatic 14,15-EET nor 14,15-DHET levels in measured compartments did not differ statistically (p = 0.21, p = 0,64, respectively). In individual patients, the levels of both eicosanoids correlated across all compartments. Conclusions: Tissue deficiency of active eicosanoids and their altered turnover may play an important role in HF pathophysiology.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Improves the Vascular Function of Arteriovenous Fistula in Rats with Hyperglycemia.

Few evidence-based medications to improve the primary patency of arteriovenous fistulas in patients with diabetes who require hemodialysis are available. We investigated whether proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) could improve arteriovenous fistula function through pleiotropic effects in a rat model of hyperglycemia. Ex vivo effects of PCSK9i on the aorta of Sprague-Dawley (SD) rats were investigated using an organ bath system. For in vivo experiments, an abdominal aortocaval (AC) fistula was generated in SD rats (200-250 g) after inducing hyperglycemia through streptozotocin administration (80 mg/kg, intraperitoneal). Alirocumab (50 mg/kg/week, subcutaneous) was administered on the day of fistula surgery and day 7. Echocardiography, blood flow through the aorta-limb, vasomotor reactivity, and serum biochemistry were examined on D14. Furthermore, enzyme-linked immunosorbent assay and immunoblotting were performed. PCSK9i induced aorta relaxation ex vivo through a potassium channel-associated mechanism. PCSK9i significantly improved blood flow and preserved endothelial function without changes in cardiac function and serum lipid levels in rats with hyperglycemia. The levels of lectin-like oxidized low-density lipoprotein receptor-1, superoxide dismutase, cyclooxygenase-2, caspase-1, and interleukin-1β were significantly reduced in the treatment group. PCSK9i decreased the ratio of phosphorylated to total p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in the aorta of rats with hyperglycemia. Short-term treatment with PCSK9i preserved endothelial function, induced vascular dilatation, and increased blood flow in the AC fistula of rats with hyperglycemia. The pleiotropic mechanisms were associated with the suppression of oxidative stress and tissue inflammation during hyperglycemia.

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.

Cardioprotective effects of Empagliflozin in cardiac volume overload-induced by aortocaval fistula in rats

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Slovak Research and Development Agency under the contract no. 21-0410 VEGA grants no. 2/0006/23 Heart failure is characterized by reduction in cardiac output and the occurrence of malignant arrhythmias, thereby contributing significantly to high morbidity and mortality worldwide. Myocardial structural remodelling is a key factor contributing to the development of these life-threatening events and belongs to unsolved clinical issues challenging to investigate in animal models. The aim of our study was to explore the impact of cardiac volume overload (VO) on structural remodelling and electrical coupling protein, connexin43 (Cx43) in the left and right heart ventricles as well as the efficacy of treatment with SGLT2i, Empagliflozin. Aortocaval fistula (ACF) was surgically induced in 6-month-old Wistar rats, to develop VO during 4 weeks, followed by oral administration of Empagliflozin 10 mg/kg/b.w. daily for 5 weeks. At the end of the experiment, biometric parameters were registered and left and right heart tissue samples were snap-frozen and kept at -80°C for western blot analysis and microscopic examination. Findings revealed an increase of heart, left and right ventricular mass due to ACF-VO versus sham controls, which was associated, with eccentric myocardial hypertrophy. Noteworthy, Empagliflozin reduced heart, left and right ventricular mass. Levels of myocardial protein Cx43, that determine electrical coupling among cardiomyocytes, were reduced by ACF-VO, while normalized by treatment with Empagliflozin. Moreover, treatment attenuated ACF-VO-induced increase of interstitial collagen visualized by van Gieson staining. It was in line with the protein expression of MMP-2, which is involved in structural remodeling. The protein levels of PKCε, concerned/associated with modulation of Cx43 and extracellular matrix, were decreased due to ACV-VO but normalized after treatment with Empagliflozin. On the other hand, protein levels of PKCδ, involved in proapoptotic and prohypertrophic pathways, were increased and normalized by Empagliflozin. The changes were more pronounced in the right ventricle compared to the left heart ventricle. In summary, our pilot results point out the benefit of Empagliflozin due to the suppression of myocardial structural remodelling and preservation of Cx43 in the rat ACF-VO model. Furthermore, this Empagliflozin-induced cardioprotection was associated with the normalization of Cx43, MMP-2, and PKC levels independent of glucose control. However, further analyses are needed to reveal the molecular mechanisms of the cardioprotective effects of Empagliflozin.

Soluble guanylate cyclase stimulator as an emerging therapeutic option in the management of arrhythmias in heart failure rat model

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This research was supported by VEGA grant no. 2/0002/20 and 2/0006/23, the Slovak Research and Development Agency under contract no. 21-0410, European Regional Development Fund: ITMS2014+: 313011AVG3. This research was also partially supported by the Ministry of Health of the Czech Republic within the project for the development of the research organization [grant number 00023001 (IKEM)—institutional support] and also supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Program EXCELES, Project No. LX22NPO5104)—Funded by the European Union—Next Generation EU Heart failure (HF) is a complex clinical syndrome characterized by a decrease in the efficiency of the heart pump, leading to a decline in hemodynamic status and cardiac remodelling, that can contribute to the formation of a substrate for arrhythmias. Antiarrhythmic drug therapy is still suboptimal and current therapies are not efficacious enough. The purpose of the current study was therefore to examine the efficiency of nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) stimulator. We used as an experimental model male hypertensive Ren-2 transgenic rats (TGR, n = 16), normotensive Hannover Sprague–Dawley rats (HSD, n = 17), and a rat model of HF surgically induced by aortocaval fistula (ACF) in rats of both strains (n = 27). After ACF induction were rats treated by sGC stimulator BAY41-8543 (3 mg/kg/day for 30 weeks) alone or combined with angiotensin-converting enzyme inhibitor (ACEi) Trandolapril (0.25 mg/kg/day for 30 weeks). Age of the animals at the end of the experiment was 40 weeks. Left ventricle tissue and plasma samples were used for further analyses. Treatment by sGC stimulator significantly decreased rats' mortality, and systolic blood pressure, and significantly increased levels of antioxidant enzyme superoxide dismutase 1, matrix metalloproteinase 2, total and phosphorylated connexin 43 as well as protein kinase C epsilon, implicated in remodelling of extracellular matrix and intercellular communication, in the left ventricle of TGR rats. Application of sGC stimulator slightly normalized elevated collagen deposition and hydroxyproline content in the left ventricular tissue of TGR rats. Unfortunately, we did not observe any effect of the sGC stimulator in the TGR ACF group. These results support the hypothesis that sGC stimulators might represent a class of drugs suitable for combating heart failure with partially anti-arrhythmic potential, but further studies are needed.

Abstract 3092: Smooth Muscle Cell Tgf-β Receptor Knockout Improves Arteriovenous Fistula Maturation Via Attenuation Of Autophagy

Objectives: Arteriovenous fistulae (AVF) are the preferred vascular access for patients with end-stage renal disease (ESRD) but have high rates of primary failure. Models of AVF using mice with chronic kidney disease (CKD) show diminished maturation and increased failure compared to AVF using wild type mice. Since mice with CKD show increased TGF-β1 expression and activity in the AVF model, and TGF-β1 signaling can alter autophagy, we hypothesized that CKD increases autophagy during AVF maturation, whereas inhibition of the smooth muscle cell (SMC) TGF-β receptor would attenuate autophagy and promote AVF maturation. Methods: An aortocaval fistula or sham procedure was created in mice that had CKD induced by 5/6 nephrectomy (5/6 Nx) or sham nephrectomy (0/6 Nx). Myh11-CreER T2 ; Tgfbr1 fl/fl ; Tgfbr2 fl/fl ; mT/mG mice (TGFβRI II-KO) and control C57BL/6J mice were used. The diameter of the IVC was determined using ultrasound at days 0, 7, 14, and 21. AVF were harvested at day 7 or 21 for histology and immunoreactivity. Deidentified human AVF and control vein specimens were collected for analysis from second stage basilic vein transpositions. Results: In C57BL/6J mice, AVF had significantly decreased diameter (p=0.0051), increased wall thickness (p=0.0002), as well as increased immunoreactivity of collagen-1 (p=0.0163), collagen-3 (p=0.0029), TGF-β1 (p=0.0184) and fibronectin (p=0.00321) in mice with CKD compared to control mice (n=6). SMC showed increased markers of autophagy (LC3B and P62) in mice with CKD compared to control mice (LC3B, p<0.0001; P62, p=0.006; n=6); similarly, autophagy makers were increased in human AVF compared with the control veins (LC3B, p=0.0023; P62, p=0.006; n=6). In SMC-TGFβR II-KO mice, AVF had significantly decreased wall thickness (p<0.0001), increased diameter (p=0.0258), and decreased expression of autophagy markers (LC3B, p=0.0014; P62, p=0.0046; n=6). Conclusion: CKD increases neointimal hyperplasia that is associated with increased autophagy during AVF failure, and diminished TGF-β signaling reduces autophagy and wall thickness as well as increases AVF diameter. Suppression of SMC autophagy might be a novel therapeutic approach to improve AFV function.

Titin's cardiac-specific N2B element is critical to mechanotransduction during volume overload of the heart

The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which has been proposed to function as a mechanosensor. To assess its significance, we conducted experiments using N2B knockout (KO) mice and wildtype (WT) mice, subjecting them to three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2) volume overload caused by aortocaval fistula (ACF), and 3) exercise-induced hypertrophy through swimming. Under conditions of pressure overload (TAC), both genotypes exhibited similar hypertrophic responses. In contrast, WT mice displayed robust left ventricular hypertrophy after one week of volume overload (ACF), while the KO mice failed to undergo hypertrophy and experienced a high mortality rate. Similarly, swim exercise-induced hypertrophy was significantly reduced in the KO mice. RNA-Seq analysis revealed an abnormal β-adrenergic response to volume overload in the KO mice, as well as a diminished response to isoproterenol-induced hypertrophy. Because it is known that the N2B element interacts with the four-and-a-half LIM domains 1 and 2 (FHL1 and FHL2) proteins, both of which have been associated with mechanotransduction, we evaluated these proteins. Interestingly, while volume-overload resulted in FHL1 protein expression levels that were comparable between KO and WT mice, FHL2 protein levels were reduced by over 90% in the KO mice compared to WT. This suggests that in response to volume overload, FHL2 might act as a signaling mediator between the N2B element and downstream signaling pathways. Overall, our study highlights the importance of the N2B element in mechanosensing during volume overload, both in physiological and pathological settings.

Abdominal aortic aneurysm complicated with aortocaval fistula

Abdominal aortic aneurysm complicated with aortocaval fistula

(707) - Renal Denervation Improves Right Ventricular Function and Restores Norepinephrine Levels in Rat Model of Heart Failure Induced by Aorto-Caval Fistula

(707) - Renal Denervation Improves Right Ventricular Function and Restores Norepinephrine Levels in Rat Model of Heart Failure Induced by Aorto-Caval Fistula