Ventricle Failure Research Articles

Exploring three-dimensional right ventricular shape and function in tetralogy of fallot patients

Abstract Background Tetralogy of Fallot (ToF) accounts for approximately 7 to 10 % of all CHD and is commonly associated with failure of the right ventricle (RV). Parameters providing more insight into the mechanics of RV failure are needed to guide clinical decision making. As advancements in Three-Dimensional (3D) echocardiography (3DE) have enabled more detailed analysis of RV volume and function, the way is paved for new 3D derived parameters. We developed a custom software to assess 3D RV shape and function. Purpose The aim of this study was to evaluate the differences of 3DE derived RV geometry (curvature) and deformation parameters in adults with ToF and controls. Methods In 50 patients with ToF and 50 controls 3DE RV images were acquired. RV geometries from 3D datasets were segmented using commercially available RV analysis software (TomTec 4D-RV function 2.0) and processed using custom software (RV-dynamics) to calculate Curvature, Area Strain (AS) and Longitudinal Strain (LS). Parameters were measured globally and over different segments of the RV (i.e. septal body (SB), inferior free wall (IFW), anterior free wall (AFW), lateral free wall (LFW), apex (Ax), RV inflow tract (RVIT), RV outflow tract (RVOT), anterior boundary (AB) and posterior boundary (PB)). Results Globally and for all independent regions of the RV, AS was significantly reduced in patients with ToF as compared with healthy controls. Except for AFW, global and all regional values of LS were significantly reduced in patients with ToF as compared with healthy controls. Global AS and LS were strongly correlated with RVEF with values for r of -0.9 and -0.6 respectively. RV curvature differed over multiple segments, predominantly in the end-diastolic Ax and end-systolic PB and Ax regions. Conclusion The RV-dynamics software gives the opportunity to analyze 3D RV morphology and RV deformation parameters in the diseased RV in more detail. AS and LS may provide more detailed assessment of the functional condition of the diseased RV in ToF whereas curvature provides an interesting method for the quantification of RV remodeling. Further insight in the different mechanisms of dysfunction of the RV may improve clinical decision making.

Sacubitril/valsartan is associated with improvements in quality of life in adult congenital heart disease patients with systemic right ventricular failure

BackgroundShort-term improvements in quality of life (QOL) have been reported in adult congenital heart disease patients with systemic right ventricle (sRV) failure after treatment with sacubitril/valsartan. This study aimed to...

1,8-Cineole reduces pulmonary vascular remodelling in pulmonary arterial hypertension by restoring intercellular communication and inhibiting angiogenesis.

Pulmonary Arterial Hypertension (PAH) is characterized by pulmonary vascular remodelling, often associated with disruption of BMPR2/Smad1/5 and BMPR2/PPAR-γ signalling pathways that ultimately lead to right ventricle failure. Disruption of intercellular junctions and communication and a pro-angiogenic environment are also characteristic features of PAH. Although, current therapies improve pulmonary vascular tone, they fail to tackle other key pathological features that could prevent disease progression. In this scenario, aromatic plants emerge as promising sources of bioactive compounds, with 1,8-cineole standing out due to its hypotensive properties and cardioprotective effect in PAH. The present study aims to explore for the first time the effect of 1,8-cineole in pulmonary vascular remodelling associated with PAH. Resorting to the monocrotaline (MCT)-induced PAH animal model, the effect of 1,8-cineole on vascular remodelling including interstitial collagen accumulation, smooth muscle cell proliferation and protein levels of BMPR2 pathway-related proteins, was assessed by microscopy and western blot (WB) analysis. The integrity of gap junctions, pulmonary surfactant, mitochondrial structure and endothelial cell barrier were evaluated by transmission electron microscopy, confocal microscopy and WB analysis. Furthermore, the effect of 1,8-cineole on angiogenesis was determined on pulmonary artery endothelial cells (PAEC) submitted to hypoxia using the scratch wound and Matrigel angiogenesis assays, and the number of sprouts on isolated healthy and diseased pulmonary artery rings, treated with the compound, enabled the validation of these effects. 1,8-Cineole mitigated PAH-associated derailment of both BMPR2/Smad1/5 and BMPR2/PPAR-γ pathways and concomitantly reduced interstitial fibrosis and the arterial medial layer thickness in pulmonary arteries. The compound restored gap junction, lung surfactant and mitochondrial integrity and preserved endothelial barrier integrity. Furthermore, 1,8-cineole exerted an anti-angiogenic effect, by impairing the formation of vessel-like structures in PAEC and sprouting formation in isolated pulmonary arteries. The present study brings new insights about the mechanisms whereby 1,8-cineole impacts pulmonary vascular remodelling and demonstrates the potential of 1,8-cineole as a therapeutic strategy to hamper PAH progression.

Sitagliptin's Effect on MALAT1 in T2DM Patients Experiencing Diastolic Failure of the Left Ventricle

Sitagliptin's Effect on MALAT1 in T2DM Patients Experiencing Diastolic Failure of the Left Ventricle

Drug therapy and catheter ablation for management of arrhythmias in continuous flow left ventricular assist device's patients: a Clinical Consensus Statement of the European Heart Rhythm Association and the Heart Failure Association of the ESC.

Left ventricular assist devices (LVADs) are an increasingly used strategy for the management of patients with advanced heart failure. Although these devices effectively improve survival, atrial and ventricular arrhythmias are common with a prevalence of 20-50% at one year after LVAD implantation. Arrhythmias predispose these patients to additional risk and are associated with considerable morbidity from recurrent implantable cardioverter-defibrillator shocks, progressive failure of the unsupported right ventricle, and herald an increased risk of mortality. Management of patients with arrhythmias and LVAD differs in many aspects from the general population heart failure patients. These include ruling out the reversible causes of arrhythmias that in LVAD patients may include mechanical irritation from the inflow cannula and suction events. For patients with symptomatic arrhythmias refractory to medical treatment, catheter ablation might be relevant. There are specific technical and procedural challenges perceived to be unique to LVAD-related ventricular tachycardia (VT) ablation such as vascular and LV access, signal filtering, catheter manoeuvrability within decompressed chambers, and electroanatomic mapping system interference. In some patients, the arrhythmogenic substrate might not be readily accessible by catheter ablation after LVAD implantation. In this regard, the peri-implantation period offers a unique opportunity to surgically address arrhythmogenic substrate and suppress future VT recurrences. This document aims to address specific aspects of the management of arrhythmias in LVAD patients focusing on anti-arrhythmic drug therapy and ablations.

Pathophysiology of Cardiorenal Syndrome in an Experimental Model Due to Isolated Right Ventricle Failure: Beyond Systemic Congestion

Pathophysiology of Cardiorenal Syndrome in an Experimental Model Due to Isolated Right Ventricle Failure: Beyond Systemic Congestion

Evaluation of Predictive Value of CT Pulmonary Angiography for Right Ventricular Failure in Patients with Pulmonary Embolism

Purpose: Right ventricle failure is a well-known complication following pulmonary thromboembolism. Although Computed Tomography Pulmonary Angiography (CTPA) findings are supposed to be a surrogate for patients’ outcome, investigations based on this issue is not still elucidated. Thus, in the current study, we assessed patients’ CTPA findings and compared the result with echocardiographic findings. Materials and Methods: A total of 36 patients with proven pulmonary thromboembolism were enrolled and a comparison was made between indices in CTPA (interventricular septal deviation to the right side, inferior vena cava contrast reflux, and right ventricle diameter to left ventricle diameter ratio) and echocardiographic findings for detecting right ventricular failure. Also, the reliability of the aforementioned indices was sought for predicting mortality. Results: No significant correlation was found between CTPA indices and echocardiographic findings. The highest sensitivity and positive predictive value in CT pulmonary angiography for detecting right ventricle dysfunction were revealed to be for Right Ventricle Diameter (RVD) / Left Ventricle Diameter (LVD) > 1 (63.64%), abnormal septal deviation (75.00%), respectively. Conclusion: Our results revealed that CTPA indices can reliably predict the upcoming mortality risk. On the other hand, these indices were not well-correlated with echocardiographic findings.

Pathogenesis and Surgical Treatment of Congenitally Corrected Transposition of the Great Arteries (ccTGA): Part III.

Congenitally corrected transposition of the great arteries (ccTGA) is an infrequent and complex congenital malformation, which accounts for approximately 0.5% of all congenital heart defects. This defect is characterized by both atrioventricular and ventriculoarterial discordance, with the right atrium connected to the morphological left ventricle (LV), ejecting blood into the pulmonary artery, while the left atrium is connected to the morphological right ventricle (RV), ejecting blood into the aorta. Due to this double discordance, the blood flow is physiologically normal. Most patients have coexisting cardiac abnormalities that require further treatment. Untreated natural course is often associated with progressive failure of the systemic right ventricle (RV), tricuspid valve (TV) regurgitation, arrhythmia, and sudden cardiac death, which occurs in approximately 50% of patients below the age of 40. Some patients do not require surgical intervention, but most undergo physiological repair leaving the right ventricle in the systemic position, anatomical surgery which restores the left ventricle as the systemic ventricle, or univentricular palliation. Various types of anatomic repair have been proposed for the correction of double discordance. They combine an atrial switch (Senning or Mustard procedure) with either an arterial switch operation (ASO) as a double-switch operation or, in the cases of relevant left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), intra-ventricular rerouting by a Rastelli procedure. More recently implemented procedures, variations of aortic root translocations such as the Nikaidoh or the half-turned truncal switch/en bloc rotation, improve left ventricular outflow tract (LVOT) geometry and supposedly prevent the recurrence of LVOTO. Anatomic repair for congenitally corrected ccTGA has been shown to enable patients to survive into adulthood.

Abstract Tu080: Unique Physiology of Fibroblast and Immune Cells in the Right Ventricle

Introduction: Failure of the right ventricle (RV) is a main component of the morbidity and mortality of pulmonary hypertension (PH). There exists no specific treatment for RV dysfunction and failure and the only cure for many patients (especially in the case of pulmonary arterial hypertension) remains transplantation. This is partially due to the critical lack of understanding of RV biology; therapeutic strategies that are beneficial for LV failure have worse outcomes when applied to those with RV failure. RV dysfunction is characterized by exaggerated fibrosis and divergent contractile and hypertrophic responses to several drugs when compared to LV dysfunction. Thus, the RV may contain distinct cellular physiology compared to the LV that has high significance for the treatment of PH. Methods: Tissue digests from the RV and LV of Sprague Dawley rats were collected. We utilized digests to collect RNA for RNA-seq, and prepared cells for flow cytometry and fibroblast isolations. Fibroblasts were cultured for proliferation assays and cell signaling studies. Results: We found that the RV and LV have significant differences in expression of immune-related and fibrotic genes. The RV of control rats had an average of four-fold higher density of immune cells, namely macrophages/monocytes, compared to the LV (P<0.05 via paired t-test). Fibroblasts from the RV of control rats, which had a higher proliferation rate and an alteration of metabolic genes than those from the LV (P<0.05 via two-way ANOVA), also had a higher fold-change increase in periostin and CTGF expression upon treatment with TGFβ. Conclusions: The results demonstrate that in comparison to the LV, the RV is made up of a unique population of cells and has a unique capacity for fibrotic response that is reflected in its molecular makeup, which may contribute to its distinct response to PH. Future experiments will focus on determining the molecular mechanisms driving these differences. This knowledge is expected to yield new therapeutic approaches for RV dysfunction and failure occurring with PH, which currently have no specific treatment.

Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function.

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.

The Role of Speckle Tracking Echocardiography in the Evaluation of Advanced-Heart-Failure Patients.

Health care is currently showing a fall in heart failure (HF) incidence and prevalence, particularly in developed countries, but with only a subset receiving appropriate therapy to protect the heart against maladaptive processes such as fibrosis and hypertrophy. Appropriate markers of advanced HF remain unidentified, which would help in choosing the most suitable therapy and avoid major compliance problems. Speckle tracking echocardiography (STE) is a good choice, being a non-invasive imaging technique which is able to assess cardiac deformation in a variety of conditions. Several multicenter studies and meta-analyses have demonstrated the clinical application and accuracy of STE in early and late stages of HF, as well as its association with both left ventricular (LV) filling pressures and myocardial oxygen consumption. Furthermore, STE assists in assessing right ventricular free-wall longitudinal strain (RVFWLS), which is a solid predictor of right ventricle failure (RVF) following LV assist device (LVAD) implantation. However, STE is known for its limitations; despite these, it has been shown to explain symptoms and signs and also to be an accurate prognosticator. The aim of this review is to examine the advantages of STE in the early evaluation of myocardial dysfunction and its correlation with right heart catheterization (RHC) parameters, which should have significant clinical relevance in the management of HF patients.

Hemodynamic evaluation of biomaterial-based surgery for Tetralogy of Fallot using a biorobotic heart, in silico, and ovine models.

Tetralogy of Fallot is a congenital heart disease affecting newborns and involves stenosis of the right ventricular outflow tract (RVOT). Surgical correction often widens the RVOT with a transannular enlargement patch, but this causes issues including pulmonary valve insufficiency and progressive right ventricle failure. A monocusp valve can prevent pulmonary regurgitation; however, valve failure resulting from factors including leaflet design, morphology, and immune response can occur, ultimately resulting in pulmonary insufficiency. A multimodal platform to quantitatively evaluate the effect of shape, size, and material on clinical outcomes could optimize monocusp design. This study introduces a benchtop soft biorobotic heart model, a computational fluid model of the RVOT, and a monocusp valve made from an entirely biological cell-assembled extracellular matrix (CAM) to tackle the multifaceted issue of monocusp failure. The hydrodynamic and mechanical performance of RVOT repair strategies was assessed in biorobotic and computational platforms. The monocusp valve design was validated in vivo in ovine models through echocardiography, cardiac magnetic resonance, and catheterization. These models supported assessment of surgical feasibility, handling, suturability, and hemodynamic and mechanical monocusp capabilities. The CAM-based monocusp offered a competent pulmonary valve with regurgitation of 4.6 ± 0.9% and a transvalvular pressure gradient of 4.3 ± 1.4 millimeters of mercury after 7 days of implantation in sheep. The biorobotic heart model, in silico analysis, and in vivo RVOT modeling allowed iteration in monocusp design not now feasible in a clinical environment and will support future surgical testing of biomaterials for complex congenital heart malformations.

Performance and Failure of Right Ventricle to Pulmonary Artery Conduit in Congenital Heart Disease

Surgical implantation of a right ventricle to pulmonary artery (RV-PA) conduit is an important component of congenital heart disease (CHD) surgery, but with limited durability, leading to re-intervention. The present single-center, retrospective, cohort study reports the results of surgically implanted RV-PA conduits in a consecutive series of children and adults with CHD. Patients with CHD referred for RV-PA conduit surgical implantation (from October 1997 to January 2022) were included. The primary outcome was conduit failure, defined as a peak gradient above 64 mm Hg, severe regurgitation, or the need for conduit-related interventions. Longitudinal echocardiographic studies were available for mixed-effects linear regression analysis. A total of 252 patients were initially included; 149 patients were eligible for follow-up data collection. After a median follow-up time of 49 months, the primary study end point occurred in 44 (29%) patients. A multivariable Cox regression model identified adult age (>18 years) at implantation and pulmonary homograft implantation as protective factors (hazard ratio 0.11, 95% confidence interval [CI] 0.02 to 0.47 and hazard ratio 0.34, 95% CI 0.16 to 0.74, respectively). Fever within 7 days of surgical conduit implantation was a risk factor for early (within 24 months) failure (odds ratio 4.29, 95% CI 1.41 to 13.01). Long-term use of oral anticoagulants was independently associated with slower progression of peak echocardiographic gradient across the conduits (mixed-effects linear regression p = 0.027). In patients with CHD, the rate of failure of surgically implanted RV-PA conduits is higher in children and after nonhomograft conduit implantation. Early fever after surgery is a strong risk factor for early failure. Long-term anticoagulation seems to exert a protective effect.

Current trends and latest developments in echocardiographic assessment of right ventricular function: load dependency perspective.

Right ventricle (RV) failure is a common complication of many cardiopulmonary diseases. Since it has a significant adverse impact on prognosis, precise determination of RV function is crucial to guide clinical management. However, accurate assessment of RV function remains challenging owing to the difficulties in acquiring its intricate pathophysiology and imaging its complex anatomical structure. In addition, there is historical attention focused exclusively on the left ventricle assessment, which has led to overshadowing and delayed development of RV evaluation. Echocardiography is the first-line and non-invasive bedside clinical tool for assessing RV function. Tricuspid annular plane systolic excursion (TAPSE), RV systolic tissue Doppler velocity of the tricuspid annulus (RV S'), and RV fractional area change (RV FAC) are conventional standard indices routinely used for RV function assessment, but accuracy has been subject to several limitations, such as load-dependency, angle-dependency, and localized regional assessment. Particularly, load dependency is a vexing issue, as the failing RV is always in a complex loading condition, which alters the values of echocardiographic parameters and confuses clinicians. Recently, novel echocardiographic methods for improved RV assessment have been developed. Specifically, "strain", "RV-pulmonary arterial (PA) coupling", and "RV myocardial work" are newly applied methods for RV function assessment, a few of which are designed to surmount the load dependency by taking into account the afterload on RV. In this narrative review, we summarize the latest data on these novel RV echocardiographic parameters and highlight their strengths and limitations. Since load independency is one of the primary advantages of these, we particularly emphasize this aspect.

Outcome of Percutaneous and Surgical Management for Tricuspid Infective Endocarditis: Insights From a National Study

BackgroundThe prevalence of infective endocarditis (IE) and its associated mortality rates remain high, despite medical advances. In recent years, treatment options for IE have expanded, but they are yet to be widely utilized. The current study aimed to compare in-hospital outcomes of high-risk tricuspid valve (TV) IE patients, by treatment strategy. MethodsPatients from the National Inpatient Sample 2017-2019 database who had TV IE were grouped by therapy type—percutaneous aspiration, surgical, or conservative management. Patients were considered to be at high risk if they underwent mechanical intervention or if they had right ventricle failure or septic emboli. ResultsThe analyzed cohort consisted of 28,495 patients—1.7% were treated with percutaneous aspiration, 13.5% with surgery, and 84.6% conservatively. Patients treated with percutaneous aspiration had the highest prevalence of septic shock and acute respiratory failure (P < 0.001). The overall in-hospital mortality rate was 7%. Patients treated conservatively had higher in-hospital mortality rates (7.5%) compared to those of the surgical group (4.4%) and the percutaneous aspiration group (4.1%; P < 0.001). In a multivariate analysis, conservative management was associated with an increased risk of in-hospital mortality (odds ratio 2.853, 95% confidence interval 1.748-4.659, P < 0.001), and no significant difference was found between the aspiration and surgical groups (P = 0.346). Benefits were pronounced in younger patients and those with septic shock or respiratory failure. Patients in the aspiration group had the highest rate of home discharge with self-care, of the various patient dispositions (P < 0.001). ConclusionsAmong high-risk patients with TV IE, an invasive approach is associated with a significantly lower in-hospital mortality rate than is a conservative approach, particularly in younger and unstable patients.

Selective inhibition of Histone deacetylases reverses vascular remodeling and improves right ventricle function in pulmonary hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Longfonds and CVON Background Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodeling of pulmonary vessels, leading to increased vascular resistance and ultimately right ventricle (RV) failure. Disturbed BMPR2/TGFβ signaling is a driver of disease progression. Inhibition of Histone deacetylases (HDACs) using small molecule inhibitors attenuated vascular remodeling, however, they worsened RV function in animal models of PAH. Objectives The aim of this study is to validate if the selective HDAC inhibitor Quisinostat reverses pulmonary vascular remodeling and improves RV function. Methods and results We found that protein levels of HDAC1 are increased in the lungs of PAH patients. Treating microvascular endothelial cells (MVECs) and smooth muscle cells of PAH patients with Quisinostat significantly decreased TGF-β signaling and strongly decreased cell proliferation and the levels of inflammatory cytokines. In the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, Quisinostat reversed abnormal vascular remodeling and improved RV function. Furthermore, Quisinostat could be combined safely with the contemporary PAH standard of care. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding, and no systemic or cardiotoxic effects were observed. Conclusions Our data demonstrate that selective inhibition of HDACs reverses pulmonary vascular remodeling and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.

THE ROLE OF MULTIPARAMETRIC EVALUATION PRIOR TO L–VAD IMPLANT IN RIGHT VENTRICLE DISFUNCTION: A CASE REPORT

Abstract Background Right ventricular failure is the most common post–operative complication after L–VAD implant and it represents an important cause of mortality in these patients. Pre–existing right ventricular disfunction is considered an absolute contraindication to L–VAD implant, though in some cases right ventricular hypokinesia could be the expression of elevated pressure in the pulmonary circulation secondary to high left heart filling pressures. Numerous clinical, echocardiographic and hemodynamic parameters have been proposed for the evaluation of L–VAD eligibility. Among these Michigan right ventricle failure score, rest and dobutamine stress echocardiography (TAPSE, S wave peak, right wall longitudinal strain) and right heart catheterization parameters showed an adequate correlation with L–VAD implant outcome. Case Report A 67 yo patient affected by advanced heart failure secondary to ischemic dilatative cardiomyopathy was referred to our unit for frequent exacerbations of heart failure despite optimal medical therapy. Echocardiography detected severe left ventricle disfunction, severe mitral regurgitation and a hypokinetic right ventricle that was not present at a previous evaluation showing only a mild disfunction. We therefore performed a dobutamine stress echocardiography to assess right ventricular contractile reserve, which demonstrated an adequate systolic response at hight dose of dobutamine (20 y/Kg/min). These data were confirmed by right heart catheterization, which allowed the evaluation of hemodynamic predictors of post L–VAD RV failure. After Heart Team discussion the L–VAD was successfully implanted. The patient was extubated at day 1 PO and weaned from inotropes at day 4, he did not present any clinical and hemodynamic signs of RV failure and is currently undergoing post–surgical rehabilitative care. Conclusions Our experience strengthen the importance of a standardized multiparametric assessment in patients affected by advanced heart failure proposed for L–VAD and showing right ventricle contractile impairment.

Extracorporeal life support after surgical repair for acute type a aortic dissection: A systematic review and meta-analysis.

The use of extracorporeal life support (ECLS) in patients after surgical repair for acute type A aortic dissection (ATAAD) has not been well documented. We performed a systematic review and meta-analysis to assess the outcomes of ECLS after surgery for ATAAD with data published by October 2023 in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. The protocol was registered in PROSPERO (CRD42023479955). Twelve observational studies met our eligibility criteria, including 280 patients. Mean age was 55.0 years and women represented 25.3% of the overall population. Although the mean preoperative left ventricle ejection fraction was 59.8%, 60.8% of patients developed left ventricle failure and 34.0% developed biventricular failure. Coronary involvement and malperfusion were found in 37.1% and 25.6%, respectively. Concomitant coronary bypass surgery was performed in 38.5% of patients. Regarding ECLS, retrograde flow (femoral) was present in 39.9% and central cannulation was present in 35.4%. In-hospital mortality was 62.8% and pooled estimate of successful weaning was 50.8%. Neurological complications, bleeding and renal failure were found in 25.9%, 38.7%, and 65.5%, respectively. ECLS after surgical repair for ATAAD remains associated with high rates of in-hospital death and complications, but it still represents a chance of survival in critical situations. ECLS remains a salvage attempt and surgeons should not try to avoid ECLS at all costs after repairing an ATAAD case.

Abstract 2109: Nox1-mediated Endothelial Ros Propagates Hypoxia-induced Pulmonary Hypertension Via The Unfolded Protein Response.

Pulmonary arterial hypertension (PAH) is a devastating disease in which reactive oxygen species (ROS) play an important role. The disease is characterized by lung arterial cell proliferation (inward remodeling) leading to right ventricle (RV) failure. We postulated that NADPH oxidase 1 (NOX1)-derived ROS mediate endothelial cell (EC) proliferation and hemodynamic changes in PAH. Indeed, we found increased NOX1 (1.6±0.10-fold; n=7-9, p&lt;0.01) in human pulmonary artery ECs (HPAECs) exposed to 24 hr hypoxia (Hx) vs. normoxia (Nx) (1% v. 21% O 2 , in vitro PAH phenotype). To test an in vivo NOX1 role, C57BL/6J (WT), mice were implanted with pumps delivering a NOX1-selective peptidic inhibitor (NoxA1ds) or scrambled control (Scr) and exposed to Nx (21% O 2 ) or Hx (10% O 2 ) for 3 wks plus vehicle or VEGF receptor antagonist Sugen 5416. Sugen/Hx (Su/Hx) increased RV max pressure (RVMP) 2-fold ± 0.20-fold (n=7-9, p&lt;0.001) along with elevated mean pulmonary artery pressure (mPAP, 2-fold 0.25-fold, n=7-9, p&lt;0.001), pulmonary vascular resistance (PVR, 2-fold±0.2-fold, n=7-9, p&lt;0.001), and right ventricular max dP/dt (RVM dP/dt, 2-fold±0.2-fold, n=7-9, p&lt;0.001) vs. Nx. NoxA1ds infusion significantly attenuated these rises. In parallel, RNA-Seq of HPAECs treated with NOX1 siRNA and exposed to Nx or Hx revealed the protein kinase R-like ER kinase (PERK) branch of the unfolded protein response (UPR) as NOX1-mediated. UPR promotes tumor growth in cancer due to positive effects on cell survival and proliferation. Indeed, phospho-PERK expression measured via WB increased by 1.5-fold ± 0.3-fold (n=9, p&lt;0.01) in HPAECs exposed to Hx, which was completely reversed by siNOX1. Further, downstream members of the PERK-UPR pathway followed similar trends including phospho-eukaryotic translation initiation factor 2A (eIF2α, 3-fold ± 0.6-fold, n=9, p&lt;0.05), activating transcription factor 4 (ATF4, 2.1-fold ± 0.4-fold, n=9, p&lt;0.01), and protein disulfide-isomerase (PDI, 2.3-fold ± 0.65-fold, n=9, p&lt;0.01). We corroborated these findings in cross-sections of Su/Hx mouse lungs and in autopsied iPAH patient lungs. The findings are consistent with NOX1 mediating activation of the UPR through PERK, which, in turn, induces EC hyperproliferation in PAH.

PDZ-Binding Kinase, a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas silencing or dominant negative PBK reduced cytokinesis and the number of cells in the G2/M phase of the cell cycle. PBK is a newly described target for PAH that is upregulated in proliferating PA smooth muscle cells, where it contributes to proliferation through changes in cytokinesis and cell cycle dynamics to promote medial thickening, fibrosis, increased PA resistance, elevated right ventricular systolic pressure, right ventricular remodeling, and PH.