Right Ventricular Heart Failure Research Articles

Myocardial Matrix Hydrogels Mitigate Negative Remodeling and Improve Function in Right Heart Failure Model

This study evaluates the effectiveness of myocardial matrix (MM) hydrogels in mitigating negative right ventricular (RV) remodeling in a rat model of RV heart failure. The goal was to assess whether a hydrogel derived from either the right or left ventricle could promote cardiac repair. Injured rat right ventricles were injected with either RV-or left ventricular-derived MM hydrogels. Both hydrogels improved RV function and morphology and reduced negative remodeling. This study supports the potential of injectable biomaterial therapies for treating RV heart failure.

Angiotensin-Converting Enzyme 2 (ACE2) Signaling in Pulmonary Arterial Hypertension: Underpinning Mechanisms and Potential Targeting Strategies.

Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling processes that lead to right-ventricular heart failure and, ultimately, death. Although our understanding of its pathophysiology has advanced and several treatment modalities are currently available for the management of PAH patients, none are curative and the prognosis remains poor. Therefore, further research is required to decipher the molecular mechanisms associated with PAH. Angiotensin-converting enzyme 2 (ACE2) plays an important role through its vasoprotective functions in cardiopulmonary homeostasis, and accumulating preclinical and clinical evidence shows that the upregulation of the ACE2/Angiotensin-(1-7)/MAS1 proto-oncogene, G protein-coupled receptor (Mas 1 receptor) signaling axis is implicated in the pathophysiology of PAH. Herein, we highlight the molecular mechanisms of ACE2 signaling in PAH and discuss its potential as a therapeutic target.

Right-Left Ventricular Interdependence in Repaired Tetralogy of Fallot Patients With Right Ventricular Heart Failure.

Patients with repaired tetralogy of Fallot (rTOF) continue to face a heightened risk of deteriorating cardiac function, and quantitative techniques of cardiac MRI-derived cardiac structure and function provide an opportunity to explore the causes and mechanisms of cardiac deterioration. To explore right-left ventricular interdependence in rTOF patients before and after the onset of right ventricular (RV) heart failure. Retrospective. One hundred eighteen rTOF patients (21.85 [16.74, 29.20] years, 58 females) and 34 controls (23.5 [21, 26.5] years, 17 females) that underwent cardiac MRI were analyzed, with rTOF patients being further subdivided into those with preserved RV function (N = 54) and those that experienced RV heart failure (N = 64). 3.0 T/balanced steady-state free precession sequence. RV, left ventricular (LV), and septal strain; RV and LV volume. Chi-squared tests or Fisher's exact test, One-way ANOVAs with Bonferroni's post hoc test, Pearson/Spearman correlation, and multivariate backward linear regression analysis. A two-tailed P < 0.05 was deemed as the significance threshold. The MRI-derived RV, LV, and septal strain decreased sequentially in controls, patients with preserved RV function, and patients with RV heart failure, with a good intra-observer (0.909-0.964) and inter-observer (0.879-0.937) agreement. Correlations between LV and RV strain were found to change sequentially with RV function and were the closest in rTOF patients with RV heart failure (r = -0.270 to 0.506). Correlations between RV volume and septal strain was variable in controls (r = 0.483 to -0.604), patients with preserved RV function (r = -0.034 to -0.295), and patients with RV heart failure (r = -0.026 to 0.500). Multivariate analyses revealed that the RV longitudinal strain was independently correlated with LV strain in three directions in rTOF patients with RV heart failure (Radial -0.70 [-1.33, -0.06]; Circumferential 0.44 [0.17, 0.72]; Longitudinal 0.54 [0.26, 0.81]). In rTOF patients, the coupling between RV volume and septal strain was broken during RV function compensation, and the adverse effect of RV on LV deformation was highest in patients with RV heart failure. 4 TECHNICAL EFFICACY: Stage 5.

Right ventricular cardiac resynchronization therapy in patients with right ventricular conduction delay and heart failure

Right ventricular cardiac resynchronization therapy in patients with right ventricular conduction delay and heart failure

Clinical Modelling of RVHF Using Pre-Operative Variables: A Direct and Inverse Feature Extraction Technique.

Right ventricular heart failure (RVHF) mostly occurs due to the failure of the left-side of the heart. RVHF is a serious disease that leads to swelling of the abdomen, ankles, liver, kidneys, and gastrointestinal (GI) tract. A total of 506 heart-failure subjects from the Faculty of Medicine, Cardiovascular Surgery Department, Ege University, Turkey, who suffered from a severe heart failure and are currently receiving support from a ventricular assistance device, were involved in the current study. Therefore, the current study explored the application of both the direct and inverse modelling approaches, based on the correlation analysis feature extraction performance of various pre-operative variables of the subjects, for the prediction of RVHF. The study equally employs both single and hybrid paradigms for the prediction of RVHF using different pre-operative variables. The visualized and quantitative performance of the direct and inverse modelling approach indicates the robust prediction performance of the hybrid paradigms over the single techniques in both the calibration and validation steps. Whereby, the quantitative performance of the hybrid techniques, based on the Nash-Sutcliffe coefficient (NC) metric, depicts its superiority over the single paradigms by up to 58.7%/75.5% and 80.3%/51% for the calibration/validation phases in the direct and inverse modelling approaches, respectively. Moreover, to the best knowledge of the authors, this is the first study to report the implementation of direct and inverse modelling on clinical data. The findings of the current study indicates the possibility of applying these novel hybridised paradigms for the prediction of RVHF using pre-operative variables.

Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity.This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

Rare and potential pathogenic mutations of LMNA and LAMA4 associated with familial arrhythmogenic right ventricular cardiomyopathy/dysplasia with right ventricular heart failure, cerebral thromboembolism and hereditary electrocardiogram abnormality

BackgroundArrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is associated with ventricular arrhythmia, heart failure (HF), and sudden death. Thromboembolism is also an important and serious complication of ARVC/D. However, the etiology of ARVC/D and thromboembolism and their association with genetic mutations are unclear.MethodsGenomic DNA samples of peripheral blood were conducted for whole-exome sequencing (WES) and Sanger sequencing in the ARVC/D family. Then, we performed bioinformatics analysis for genes susceptible to cardiomyopathies and arrhythmias. Further, we analyzed how the potential pathogenic mutations were affecting the hydrophobicity and phosphorylation of amino acids and their joint pathogenicity by ProtScale, NetPhos and ORVAL algorisms.ResultsWe discovered a Chinese Han family of ARVC/D with right ventricular HF (RVHF), cerebral thromboembolism, arrhythmias (atrial fibrillation, atrial standstill, multifocal ventricular premature, complete right bundle block and third-degree atrioventricular block) and sudden death. Based on the WES data, the variants of LMNA p.A242V, LAMA4 p.A225P and RYR2 p.T858M are highly conserved and predicated as “deleterious” by SIFT and MetaSVM algorithms. Their CADD predicting scores are 33, 27.4 and 25.8, respectively. These variants increase the hydrophobicity of their corresponding amino acid residues and their nearby sequences by 0.378, 0.266 and 0.289, respectively. The LAMA4 and RYR2 variants lead to changes in protein phosphorylation at or near their corresponding amino acid sites. There were high risks of joint pathogenicity for cardiomyopathy among these three variants. Cosegregation analysis indicated that LMNA p.A242V might be an important risk factor for ARVC/D, electrocardiogram abnormality and cerebral thromboembolism, while LAMA4 p.A225P may be a pathogenic etiology of ARVC/D and hereditary electrocardiogram abnormality.ConclusionsThe LMNA p.A242V may participate in the pathogenesis of familial ARVC/D with RVHF and cerebral thromboembolism, while LAMA4 p.A225P may be associated with ARVC/D and hereditary electrocardiogram abnormality.

Acute Cholecystitis Masking Right-Sided Heart Failure: A Near-Miss Event

<h3>Introduction</h3> Pulmonary hypertension (PAH) may lead to progressive right-ventricular (RV) heart failure with symptoms of hypervolemia such as renal or hepatic congestion. We present a case of a critically ill patient presenting as sepsis from acute cholecystitis, which was later unmasked as RV failure due to uncontrolled PAH. <h3>Case Report</h3> A 67-year-old female with known PAH presented with 4 days of right upper quadrant abdominal pain and emesis. She was tachycardic and hypotensive. CT imaging showed a thick, fluid-filled gallbladder with ascites concerning for acute cholecystitis. Lab testing revealed a lactic acid of 10 and leukocytosis of 11,000. She was managed with IV antibiotics and planned for surgery, until a bedside echocardiogram showed a dilated RV and RA with severe tricuspid regurgitation. A catheterization confirmed severely elevated right heart pressures. She was started on IV treprostinil, milrinone, and diuretics with resolution of lactic acidosis and abdominal pain. <h3>Decision Making</h3> The patient's history of PAH along with evidence of hypervolemia led to suspicion of acute RV failure as the cause of cholecystitis. This led to changes in management by holding IV fluids as would otherwise be indicated in sepsis and prompting an urgent echocardiogram and heart catheterization. The diagnosis was confirmed and she was started on appropriate therapy. <h3>Summary</h3> Understanding complications of PAH and acute RV failure, which can produce symptoms similar to an acute abdominal syndrome, may prompt early appropriate interventions and prevent potentially harmful management.

Using computational methods to design patient-specific electrospun cardiac patches for pediatric heart failure

Autologous cardiac cell therapy is a promising treatment for combating the right ventricular heart failure (RVHF) that can occur in patients with congenital heart disease (CHD). However, autologous cell therapies suffer from low cell retention following injection and patient-to-patient variability in cell quality. Here, we demonstrate how computational methods can be used to identify mechanisms of cardiac-derived c-Kit+ cell (CPC) reparative capacity and how biomaterials can be designed to improve cardiac patch performance by engaging these mechanisms. Computational modeling revealed the integrin subunit αV (ITGAV) as an important mediator of repair in CPCs with inherently low reparative capacity (CPCslow). We could engage ITGAV on the cell surface and improve reparative capacity by culturing CPCs on electrospun polycaprolactone (PCL) patches coated with fibronectin (PCL + FN). We tested CPCs from 4 different donors and found that only CPCslow with high ITGAV expression (patient 956) had improved anti-fibrotic and pro-angiogenic paracrine secretion on PCL + FN patches. Further, knockdown of ITGAV via siRNA led to loss of this improved paracrine secretion in patient 956 on PCL + FN patches. When implanted in rat model of RVHF, only PCL + FN + 956 patches were able to improve RV function, while PCL +956 patches did not. In total, we demonstrate how cardiac patches can be designed in a patient-specific manner to improve in vitro and in vivo outcomes.

Hemodynamics-driven mathematical model of first and second heart sound generation.

We propose a novel, two-degree of freedom mathematical model of mechanical vibrations of the heart that generates heart sounds in CircAdapt, a complete real-time model of the cardiovascular system. Heart sounds during rest, exercise, biventricular (BiVHF), left ventricular (LVHF) and right ventricular heart failure (RVHF) were simulated to examine model functionality in various conditions. Simulated and experimental heart sound components showed both qualitative and quantitative agreements in terms of heart sound morphology, frequency, and timing. Rate of left ventricular pressure (LV dp/dtmax) and first heart sound (S1) amplitude were proportional with exercise level. The relation of the second heart sound (S2) amplitude with exercise level was less significant. BiVHF resulted in amplitude reduction of S1. LVHF resulted in reverse splitting of S2 and an amplitude reduction of only the left-sided heart sound components, whereas RVHF resulted in a prolonged splitting of S2 and only a mild amplitude reduction of the right-sided heart sound components. In conclusion, our hemodynamics-driven mathematical model provides fast and realistic simulations of heart sounds under various conditions and may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.New & noteworthyTo the best of our knowledge, this is the first hemodynamic-based heart sound generation model embedded in a complete real-time computational model of the cardiovascular system. Simulated heart sounds are similar to experimental and clinical measurements, both quantitatively and qualitatively. Our model can be used to investigate the relationships between heart sound acoustic features and hemodynamic factors/anatomical parameters.

Right ventricular systolic function in severe tricuspid regurgitation: prognostic relevance of longitudinal strain.

The aim of this study is to analyse the prognostic implications of right ventricular (RV) dysfunction as detected by strain analysis in patients with severe tricuspid regurgitation (TR). The evaluation of RV systolic function in presence of severe TR is of paramount importance for operative risk stratification; however, it remains challenging, as conventional echocardiographic indexes usually lead to overestimation. We enrolled 250 consecutive patients with severe TR referred to our centre. Baseline clinical and echocardiographic data and follow-up outcomes were collected. Patients were predominantly female, with multiple cardiovascular risk factors and comorbidities, history of heart failure, and atrial fibrillation. Most of them had presented with clinical signs of RV heart failure (RVHF) and advanced New York Heart Association class. The RV strain analysis [both RV free wall longitudinal strain (RVFWLS) and RV global longitudinal strain (RVGLS)] reclassified ∼42-56% of patients with normal RV systolic function according to conventional parameters in patients with impaired RV systolic function. RVFWLS ≤17% (absolute values, AUC: 0.66, P = 0.002) predicted the presence of RVHF [odds ratio (OR) 0.93, P = 0.01]. At follow-up, patients with RVFWLS >14% (absolute values, AUC: 0.70, P = 0.001, sensitivity 72%, specificity 54%) showed a better survival (P = 0.01). Different ranges of RVFWLS have different implications in patients with severe TR, allowing to identify a preclinical and a clinical window, with correlations to RVHF and survival.

Strengthening multidisciplinary collaboration and promoting the construction of standardized system for pulmonary hypertension in China

In recent years, pulmonary hypertension (PH) has attracted increasing attention from scholars worldwide, which involves diverse etiology and complicated pathogenesis. Due to changes in the structure and function of pulmonary vasculatures, it can lead to an increase in pulmonary vascular resistance and pulmonary artery pressure, and then progress to right ventricular heart failure or even death. The diagnosis of PH involves multiple disciplines, which could easily give rise to missed diagnosis and misdiagnosis and non-standardized treatment. Recently, we have made great progress in the field of clinical diagnosis, treatment and research of PH. However, many issues remain to be solved. Accordingly, this article aims to call for further strengthening of multidisciplinary collaboration in PH field and promote the construction of a standardized system for PH in China.

Electrical Stimulation of pediatric cardiac-derived c-kit+ progenitor cells improves retention and cardiac function in right ventricular heart failure.

Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac‐derived c‐kit+ progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES‐CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of β1 and β5 integrins contributed to the increased retention of ES‐CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro‐reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c‐kit+ progenitor cells and can have implications on a variety of cell‐based therapies. stem cells 2019;37:1528–1541

Predicting Functional Responses of Progenitor Cell Exosome Potential with Computational Modeling.

Congenital heart disease can lead to severe right ventricular heart failure (RVHF). We have shown that aggregated c‐kit+ progenitor cells (CPCs) can improve RVHF repair, likely due to exosome‐mediated effects. Here, we demonstrate that miRNA content from monolayer (2D) and aggregated (3D) CPC exosomes can be related to in vitro angiogenesis and antifibrosis responses using partial least squares regression (PLSR). PLSR reduced the dimensionality of the data set to the top 40 miRNAs with the highest weighted coefficients for the in vitro biological responses. Target pathway analysis of these top 40 miRNAs demonstrated significant fit to cardiac angiogenesis and fibrosis pathways. Although the model was trained on in vitro data, we demonstrate that the model can predict angiogenesis and fibrosis responses to exosome treatment in vivo with a strong correlation with published in vivo responses. These studies demonstrate that PLSR modeling of exosome miRNA content has the potential to inform preclinical trials and predict new promising CPC therapies. stem cells translational medicine 2019;8:1212–1221

Abstract 415: Electrical Stimulation of Pediatric Cardiac-derived c-kit + Progenitor Cells Improves Retention and Cardiac Function in Right Ventricular Heart Failure

Nearly 1% of babies born in the US will be diagnosed with a congenital heart defect (CHD). While surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. While primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Cardiac-derived c-kit + progenitor cells (CPCs) have been widely studied as a cell-based therapy for cardiac pathologies; however, unless these cells are extracted at a very young age their therapeutic efficacy has been shown to be diminished. Finding novel ways to enhance the reparative potential of these cells is thus of critical significance. We previously reported pediatric CPCs (isolated from patients between 1-5 years of age) respond to electrical stimulation (ES) by initiating intracellular calcium oscillations. Here, we investigate the ability of ES to enhance the retention and therapeutic function of pediatric CPCs in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes, such as integrins β1 and β5, and significantly increased in vitro survival and adhesion of cells. Lastly, we show that ES induces CPCs to release higher levels of reported pro-reparative factors in vitro, including angiogenin, FGF, HGF, and VEGF. These findings suggest electrical stimulation can be utilized to increase the retention, survival, and therapeutic effect of human c- kit + progenitor cells. Furthermore, our insights into the mechanisms of increased retention and paracrine function of ES-CPCs can have implications on a variety of cell-based therapies.

Electrospun Nanofiber-Based Patches for the Delivery of Cardiac Progenitor Cells.

Congenital heart disease is the number one cause of birth defect-related death because it often leads to right ventricular heart failure (RVHF). One promising avenue to combat this RVHF is the use of cardiac patches composed of stem cells and scaffolds. Herein, we demonstrate a reparative cardiac patch by combining neonatal or child c-kit+ progenitor cells (CPCs) with a scaffold composed of electrospun polycaprolactone nanofibers. We examined different parameters of the patch, including the alignment, composition, and surface properties of the nanofibers, as well as the age of the CPCs. The patch based on uniaxially aligned nanofibers successfully aligned the CPCs. With the inclusion of gelatin in the nanofiber matrix and/or coating of fibronectin on the surface of the nanofibers, the metabolism of both neonatal and child CPCs was generally enhanced. The conditioned media collected from both patches based on aligned and random nanofibers could reduce the fibrotic gene expression in rat cardiac fibroblasts, following stimulation with transforming growth factor β. Furthermore, the conditioned media collected from the nanofiber-based patches could lead to the formation of tubes of human umbilical vein endothelial cells, indicating the pro-angiogenic capability of the patch. Taken together, the electrospun nanofiber-based patches are a suitable delivery vehicle for CPCs and can confer reparative benefit through anti-fibrotic and pro-angiogenic paracrine signaling.

Aggregation of Child Cardiac Progenitor Cells Into Spheres Activates Notch Signaling and Improves Treatment of Right Ventricular Heart Failure.

Congenital heart disease can lead to life-threatening right ventricular (RV) heart failure. Results from clinical trials support expanding cardiac progenitor cell (CPC) based therapies. However, our recent data show that CPCs lose function as they age, starting as early as 1 year. To determine whether the aggregation of child (1-5-year-old) CPCs into scaffold-free spheres can improve differentiation by enhancing Notch signaling, a known regulator of CPC fate. We hypothesized that aggregated (3-dimensional [3D]) CPCs will repair RV heart failure better than monolayer (2-dimensional [2D]) CPCs. Spheres were produced with 1500 CPCs each using a microwell array. CPC aggregation significantly increased gene expression of Notch1 compared with 2D CPCs, accompanied by significant upregulation of cardiogenic transcription factors (GATA4, HAND1, MEF2C, NKX2.5, and TBX5) and endothelial markers (CD31, FLK1, FLT1, VWF). Blocking Notch receptor activation with the γ-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) diminished these effects. To evaluate the therapeutic improvements of CPC aggregation, RV heart failure was induced in athymic rats by pulmonary artery banding, and cells were implanted into the RV free wall. Echocardiographic measurements 28 days postimplantation showed significantly improved RV function with 3D compared with 2D CPCs. Tracking implanted CPCs via DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide)-labeling showed improved retention of 3D CPCs. Transducing 3D CPCs with Notch1-shRNA (short hairpin RNA) did not reduce retention, but significantly reduced RV functional improvements. Histological analyses showed 3D treatment reduced RV fibrosis and increased angiogenesis. Although 3D CPCs formed CD31+ vessel-like cells in vivo, these effects are more likely because of improved 3D CPC exosome function compared with 2D CPC exosomes. Spherical aggregation improves child CPC function in a Notch-dependent manner. The strong reparative ability of CPC spheres warrants further investigation as a treatment for pediatric heart failure, especially in older children where reparative ability may be reduced.

Right coronary artery ligation in mice: a novel method to investigate right ventricular dysfunction and biventricular interaction.

Right ventricular (RV) dysfunction can lead to complications after acute inferior myocardial infarction (MI). However, it is unclear how RV failure after MI contributes to left-sided dysfunction. The aim of the present study was to investigate the consequences of right coronary artery (RCA) ligation in mice. RCA ligation was performed in C57BL/6JRj mice ( n = 38). The cardiac phenotypes were characterized using high-resolution echocardiography performed up to 4 wk post-RCA ligation. Infarct size was measured using 2,3,5-triphenyltetrazolium chloride staining 24 h post-RCA ligation, and the extent of the fibrotic area was determined 4 wk after MI. RV dysfunction was confirmed 24 h post-RCA ligation by a decrease in the tricuspid annular plane systolic excursion ( P < 0.001) and RV longitudinal strain analysis ( P < 0.001). Infarct size measured ex vivo represented 45.1 ± 9.1% of the RV free wall. RCA permanent ligation increased the RV-to-left ventricular (LV) area ratio ( P < 0.01). Septum hypertrophy ( P < 0.01) was associated with diastolic septal flattening. During the 4-wk post-RCA ligation, LV ejection fraction was preserved, yet it was associated with impaired LV diastolic parameters ( E/ E', global strain rate during early diastole). Histological staining after 4 wk confirmed the remodeling process with a thin and fibrotic RV. This study validates that RCA ligation in mice is feasible and induces RV heart failure associated with the development of LV diastolic dysfunction. Our model offers a new opportunity to study mechanisms and treatments of RV/LV dysfunction after MI. NEW & NOTEWORTHY Right ventricular (RV) dysfunction frequently causes complications after acute inferior myocardial infarction. How RV failure contributes to left-sided dysfunction is elusive because of the lack of models to study molecular mechanisms. Here, we created a new model of myocardial infarction by permanently tying the right coronary artery in mice. This model offers a new opportunity to unravel mechanisms underlying RV/left ventricular dysfunction and evaluate drug therapy.

Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure.

Children with congenital heart diseases have increased morbidity and mortality, despite various surgical treatments, therefore warranting better treatment strategies. Here we investigate the role of age of human pediatric cardiac progenitor cells (hCPCs) on ventricular remodeling in a model of juvenile heart failure. hCPCs isolated from children undergoing reconstructive surgeries were divided into 3 groups based on age: neonate (1 day to 1 month), infant (1 month to 1 year), and child (1 to 5 years). Adolescent athymic rats were subjected to sham or pulmonary artery banding surgery to generate a model of right ventricular (RV) heart failure. Two weeks after surgery, hCPCs were injected in RV musculature noninvasively. Analysis of cardiac function 4 weeks post-transplantation demonstrated significantly increased tricuspid annular plane systolic excursion and RV ejection fraction and significantly decreased wall thickness and fibrosis in rats transplanted with neonatal hCPCs compared with saline-injected rats. Computational modeling and systems biology analysis were performed on arrays and gave insights into potential mechanisms at the microRNA and gene level. Mechanisms including migration and proliferation assays, as suggested by computational modeling, showed improved chemotactic and proliferative capacity of neonatal hCPCs compared with infant/child hCPCs. In vivo immunostaining further suggested increased recruitment of stem cell antigen 1-positive cells in the right ventricle. This is the first study to assess the role of hCPC age in juvenile RV heart failure. Interestingly, the reparative potential of hCPCs is age-dependent, with neonatal hCPCs exerting the maximum beneficial effect compared with infant and child hCPCs. Stem cell therapy for children with congenital heart defects is moving forward, with several completed and ongoing clinical trials. Although there are studies showing how children differ from adults, few focus on the differences among children. This study using human cardiac progenitor cells shows age-related changes in the reparative ability of cells in a model of pediatric heart failure and uses computational and systems biology to elucidate potential mechanisms.

0190: Predictive factors of intrahospital mortality in patients with right ventricular myocardial infarction

Right ventricular (RV) infarction is a serious and life threatening condition which mainly complicates an inferior wall myocardial infarction (MI). In the literature, data for predictive factors of mortality in this setting remains scarce. Aim to study predictive factors of intrahospital mortality in patients with RV infarction. Data was collected from a monocenter registry including all patients with AMI admitted in our department between January 1995 and March 2013. 1483 patients were enrolled in our registry. RV infarction was diagnosed in 160 (10.7%) patients, always complicating an inferior wall MI. 37 (23.1%) patients presented with right sided heart failure while the remaining patients presented with isolated features of RV involvement on the ECG with ST elevation in the right leads. Intrahospital death occurred in 20 patients (12.5%) and was significantly higher in patients with RV heart failure (p=0.02). Among all deaths included in our registry, RV infarction was responsible for 14.5%. The reperfusion strategy was Thrombolysis in 48 patients (30%), angioplasty in 62 patients (38.8%), a combined approach in 10 cases (6.3%) and conservative treatment in 40 cases (25%). There was no difference in mortality among all strategies (p: 0.556). In patients who had angioplasty, post procedural TIMI flow 0 or 1 was associated with a higher mortality (p<0.001). In a multivariate analysis, factors found to predict intra-hospital mortality were: renal impairment defined as creatinin levels >130umol/l (OR: 8.22; 95% CI [1.33-50.9]; p: 0.023), triple vessel disease (OR: 7.09; 95% CI [1.738-28.93]; p: 0.006) and left ventricular failure with KILLIP >1 (p: 0.004). Our data support the fact that several factors may predict intra-hospital mortality after RV myocardial infarction among which renal impairment, the extent of coronary artery disease and left ventricular heart failure are most the powerful predictors.