Impaired Ventricular Relaxation Research Articles

Effects of the restrictive cardiomyopathy-associated cardiac troponin I K178E mutation on cAMP signalling at the myofilament

Abstract Background Catecholaminergic stimulation of cardiac β-adrenergic receptors (β-ARs) and subsequent cAMP signalling control cardiac inotropy and lusitropy. cAMP signalling is known to be compartmentalised to optimise sympathetic control by producing heterogeneous cAMP signals and protein kinase A (PKA) activation at distinct subcellular sites. This signalling may be disrupted in diseases such as restrictive cardiomyopathy (RCM) characterised by diastolic dysfunction, which is associated with certain mutations including the K178E missense mutation in cardiac troponin I (TPNI). The impaired ventricular relaxation associated with this mutation is thought to arise from myofilament calcium hypersensitivity, which can be modulated by PKA-dependent TPNI phosphorylation. However, a detailed understanding of the pathological effects mediated by the K178E-TPNI mutation is lacking. Purpose This study aims to determine whether the K178E-TPNI mutation alters local cAMP/PKA signalling at TPNI, potentially affecting myofilament calcium sensitivity and cardiac myocyte relaxation. Methods Real-time imaging of cAMP was carried out using the Fluorescence Resonance Energy Transfer (FRET)-based sensor CUTie (cAMP Universal Tag for imaging experiments) [1] fused to wild type (WT)- or K178E-TPNI. The sensors were expressed by transfection in neonatal rat ventricular myocytes (NRVMs) and FRET-changes were recorded at the myofilament on application of the β-AR stimulant isoproterenol (ISO). We further assessed the involvement of cAMP hydrolysing phosphodiesterases (PDEs) in the regulation of cAMP levels selectively at TPNI. Results The peak FRET-change and FRET-change after 5mins on ISO application were significantly higher in NRVMs expressing the mutant compared to the WT sensor, as was the rate of cAMP accumulation. A strong trend showed that the rise in FRET following PDE4 inhibition was larger in NRVMs expressing the WT compared to the mutant sensor, suggesting the involvement of this isoform in degrading cAMP locally at TPNI and reduced PDE4 activity in the presence of the K178E mutation. Co-immunoprecipitation analysis in HEK293 cells demonstrated interaction between WT-TPNI and a PDE4D isoform, and a weaker interaction of this isoform with the K178E-TPNI mutant. Conclusions This study shows that the K178E-TPNI mutation attenuates the TPNI/PDE4D interaction and alters the magnitude and kinetics of the local cAMP response at the myofilament. This mechanistic insight may aid the development of therapeutics targeting the TPNI/PDE4D interaction to treat RCM-associated diastolic dysfunction.The TPNI-CUTie SensorFRET Response Trace

Pharmacological research progress of five classical prescriptions in treatment of chronic heart failure

Chronic heart failure(CHF) is a comprehensive clinical syndrome caused by multiple factors that result in structural and/or functional abnormalities of the heart, leading to impaired ventricular contraction and/or relaxation functions. This medical condition represents the final stage of various cardiovascular diseases. In the treatment of CHF, multiple clinical studies have demonstrated the benefits of using traditional Chinese medicine(TCM) to control oxidative stress, inflammation, and apoptosis, thereby delaying ventricular remodeling and reducing myocardial fibrosis. In this study, common TCM syndromes in the diagnosis and treatment of CHF in recent years were reviewed and summarized. Five common treatment methods including benefiting Qi and activating blood circulation, enhancing Qi and nourishing Yin, warming Yang for diuresis, eliminating phlegm and dampness, rescuing from collapse by restoring Yang, and corresponding classic prescriptions in prevention and treatment of CHF were concluded under the guidance of TCM syndrome differentiation thinking. Meanwhile, research progress on the modern pharmacological effects of these classic prescriptions was systematically discussed, so as to establish a unique treatment system for CHF by classic prescriptions under the guidance of TCM syndrome differentiation theory and provide innovative diagnosis and treatment strategies for clinical CHF.

Defining the Phenotypes for Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) imposes a significant burden on society and healthcare. The lack in efficacious therapies is likely due to the significant heterogeneity of HFpEF. In this review, we define various phenotypes based on underlying comorbidities or etiologies, discuss phenotypes arrived at by novel methods, and explore therapeutic targets. A few studies have used machine learning methods to uncover sub-phenotypes within HFpEF in an unbiased manner based on clinical features, echocardiographic findings, and biomarker levels. We synthesized the literature and propose three broad phenotypes: (1) young, with few comorbidities, usually obese and with low natriuretic peptide levels, (2) obese with substantive cardiometabolic burden and comorbidities and impaired ventricular relaxation, (3) old, multimorbid, with high rates of atrial fibrillation, renal and coronary artery disease, chronic obstructive pulmonary disease, and left ventricular hypertrophy. We also propose potential therapeutic strategies for these phenotypes.

Overview of Restrictive Cardiomyopathies.

Restrictive cardiomyopathy (RCM) includes a heterogeneous group of diseases that cause increased myocardial stiffness, leading to impaired ventricular relaxation and severe diastolic dysfunction. Given that it is the least common type of cardiomyopathy, it can be a diagnostic challenge due to its varied pathogenesis, clinical presentation, and diagnostic evaluation. In this review, we provide an overview of different etiologies of RCM and examine the diagnostic and treatment approaches for various types.

Peri-operative changes in diastolic function and outcomes in congenital aortic valve surgery.

BackgroundThe ratio of early diastolic mitral inflow velocity (E) to early diastolic mitral annular tissue velocity (e’), or E/e’, is an echocardiographic measure of left ventricular filling pressure. Peri‐operative changes in E/e’ and association with outcomes have been demonstrated in adults undergoing surgery for aortic stenosis (AS). We sought to explore changes in E/e’ and other diastolic indices in the setting of congenital AS surgery and to assess for association with post‐operative outcomes among children and young adults.MethodsA retrospective, single‐center study was performed among patients 6 months to 30 years of age who underwent congenital AS surgery from 2006 to 2018. Tissue Doppler indices were collected from pre‐ and post‐operative echocardiograms. Post‐operative outcomes were reviewed.ResultsSixty‐six subjects with subvalvar (45%), valvar (47%), and supravalvar (8%) AS underwent surgery at a median age of 9.5 years (IQR: 4.0–14.8). Pre‐operatively, the lateral E/e’ ratio was 8.6 (6.7–11.0); 33% had E/e’≥10. Post‐operatively, the lateral e’ decreased to 9.9 cm/s (8.0–11.4), the E/e’ ratio increased to 10.4 (8.3–13.1); and 53% had E/e’≥10 (p‐values < 0.0001, 0.0072, and < 0.001, respectively). Pre‐operative lateral e’ correlated modestly with duration of intubation (ρ = −0.24, p‐value 0.048) and post‐operative lateral e’ correlated modestly with duration of intubation and length of hospital stay (ρ = −0.28 and −0.26, p‐values = 0.02 and 0.04, respectively).ConclusionsChildren and young adults who underwent congenital AS surgery had echocardiographic evidence of diastolic dysfunction pre‐operatively that worsened post‐operatively. Lateral e’ may be a sensitive indicator of impaired ventricular relaxation in these patients and may impact duration of intubation and hospital stay.

Cardiac Fibroblasts Play Pathogenic Roles in Idiopathic Restrictive Cardiomyopathy.

Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation. Although several mutations were reported in some patients, no mutations were identified in cardiomyocyte expressing genes of other patients, indicating that pathological mechanisms underlying RCM could not be determined by cardiomyocytes only. Cardiac fibroblasts (CFs) are a major cell population in the heart; however, the pathological roles of CFs in cardiomyopathy are not fully understood.Methods and Results:This study established 4 primary culture lines of CFs from RCM patients and analyzed their cellular physiology, the effects on the contraction and relaxation ability of healthy cardiomyocytes under co-culture with CFs, and RNA sequencing. Three of four patients hadTNNI3mutations. There were no significant alterations in cell proliferation, apoptosis, migration, activation, and attachment. However, when CFs from RCM patients were co-cultured with healthy cardiomyocytes, the relaxation velocity of cardiomyocytes was significantly impaired both under direct and indirect co-culture conditions. RNA sequencing revealed that gene expression profiles of CFs in RCM were clearly distinct from healthy CFs. The differential expression gene analysis identified that several extracellular matrix components and cytokine expressions were dysregulated in CFs from RCM patients. The comprehensive gene expression patterns were altered in RCM-derived CFs, which deteriorated the relaxation ability of cardiomyocytes. The specific changes in extracellular matrix composition and cytokine secretion from CFs might affect pathological behavior of cardiomyocytes in RCM.

Prevalence and correlates of diastolic dysfunction in patients with hypertension: a cross-sectional study from in The Kingdom of Saudi Arabia.

Introductiondiastolic dysfunction refers to impaired ventricular relaxation or filling regardless of ejection fraction and symptoms. It accounts for 8% and 25% in the hospitalized and general population, respectively. The present study was conducted to determine the prevalence and correlates of diastolic dysfunction in hypertensive patients living in Saudi Arabia.Methodsa multicentric, cross-sectional study was conducted from February 2019 to February 2020 at King Khalid Hospital and Prince Sultan Center for Health Services, Prince Sattam Bin Abdulaziz University hospital in Al Kharj, and Al Kharj Military Industries Corporation hospital, KSA. All patients with hypertension who underwent an echocardiography were included in the study. Logistic regression analysis was performed to determine factors associated with left ventricular diastolic dysfunction (LVDD).Resultsthe study included a total of 104 participants, where 51.9% were females and the mean age of the patients was 48.01±12.81 years. Most patients had an abnormal echocardiography finding (64.4%, n = 67). The most common abnormalities were left ventricular (LV) hypertrophy (44.2%, n = 46), and diastolic dysfunction, (35.6%, n = 37). The study revealed that age (aOR: 6.1, 95% CI 1.17-31.3; p = 0.032) and dyslipidemia (aOR: 3.45, 95% CI 1.16-10.24; p = 0.026) have significant association with LVDD in the patients with hypertension.Conclusionin conclusion, diastolic dysfunction is prevalent among older hypertensive patients and those with dyslipidaemia. Age and dyslipidaemia were non-modifiable and modifiable factors associated with LVDD in hypertensive patients, respectively.

Relationship of left ventricular and atrial dimensions with moderate to severe left ventricular diastolic dysfunction (grade II and above).

Left ventricular diastolic dysfunction (DD) is an entity in which the ventricle fails to fill up properly due to impaired ventricular relaxation and/or decreased compliance. The diagnosis of diastolic dysfunction is based on a variety of parameters in doppler echocardiograpy. However, some parameters like interventricular septal thickness in diastole (IVSd), posterior wall thickness in diastole (PWd), left ventricular internal end diastolic and systolic diameters (LVIDD and LVISD) along with left atrial diameters (LAD) have yet to be evaluated for the diagnostic workup of DD. A case control study was done in the cardiology department from patient records from 2016 to 2018. Patients were diagnosed as diastolic dysfunction grade II and above by doppler echocardiography. IVSd, PWd, LVIDD, LAD, LVISD were obtained through 2-D echocardiography. Patients with DD had greater LAD, IVSd and PWd and decreased LVIDD and LVISD as compared to control group. Overall, IVSD was the most significant predictor (OR 1.52 95%CI 1.35-1.71) of DD followed by PWd and LAD. Similarly, LAD, IVSd and PWd had higher sensitivity and specificity than LVIDD and LVIDS. IVSd, LAD and PWd showed significant performance in the diagnosis of diastolic dysfunction and hence can be used as a screening and diagnostic tool in diastolic dysfunction of grade ll and above.

Distinguishing HF with reduced and preserved ejection fraction at the level of individual cardiomyocytes: implications for therapeutic development

Distinguishing HF with reduced and preserved ejection fraction at the level of individual cardiomyocytes: implications for therapeutic development

Diagnostic and Prognostic Utilities of Insulin-Like Growth Factor Binding Protein-7 in Patients With Dyspnea

ObjectivesThis study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration. BackgroundIGFBP7 is associated with impaired ventricular relaxation and worse prognosis. MethodsThe ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained. ResultsAmong 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p < 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p < 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p < 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher log2-IGFBP7 concentrations in patients with acute HF predicted death or rehospitalization at 6 months (hazard ratio: 1.84 per log2-SD; 95% confidence interval: 1.30 to 2.61; p = 0.001). In Kaplan-Meier analyses, supramedian concentrations of IGFBP7 were associated with shorter event-free survival (log-rank: p < 0.001). ConclusionsAmong patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

A Coupled Electromechanical Myocyte Model to Assess the Effects of 2‐deoxy‐ATP on Contractile Function in the Heart

IntroductionHeart failure (HF) remains a significant cause of morbidity, mortality, and medical costs. HF is characterized by reduced contractile function and inability of the heart to pump sufficient blood to meet the body’s demands. Existing treatments for HF do not permanently restore cardiac function and can lead to side effects such as impaired ventricular relaxation. 2‐deoxy‐ATP (dATP), a novel heart failure therapeutic, has been shown to increase contractile function while enhancing relaxation [1]. Previous studies have shown that dATP increases the rate of crossbridge cycling [2]. It has also been shown that dATP acts on the sarcoplasmic reticulum ATPase (SERCA), the pump responsible for removing calcium (Ca2+) from the cytosol, which could explain the enhanced relaxation kinetics seen experimentally [3]. However, the mechanism of dATP is still not fully understood. Further, it is not clear whether the increased rate of crossbridge cycling with dATP treatment could aggravate energy starvation in HF.MethodsTo assess the full mechanism of dATP at the cellular level, we utilized a myocyte model containing several ion channels, including SERCA [4]. We coupled this model to a mitochondria model to investigate whether dATP treatment aggravates energy starvation by tracking ATP, ADP, Pi, and oxygen concentrations over time [5]. We also coupled the myocyte model to a previously developed 5 state Markov model of crossbridge cycling, which captures regulation of contraction via Ca2+ binding to troponin [2]. The crossbridge cycling model was modified to capture the effects of sarcomere length on Ca2+ sensitivity. dATP treatment was simulated by adjusting the ATP and Ca2+ binding rates in the SERCA model and the rate of crossbridge cycling in the sarcomere model based on previous studies [2, 3].Results and ConclusionsWe found that the combined effects of dATP on both SERCA and the sarcomere within the coupled myocyte model could explain the increase in fractional shortening and time to 50% and 90% relaxation of the Ca2+ transient seen experimentally more accurately than either model alone. Additionally, we found no evidence that dATP aggravates energy starvation, affirming dATP as a promising therapeutic for HF.Support or Funding InformationNIH HLT32 TG

Association between right heart diastolic function and clinical presentation of chronic venous disease and primary varicose veins of lower extremities.

This study examines the association between right heart diastolic function and clinical presentation of chronic venous disease and primary varicose veins of lower extremities. We performed retrospective analysis of clinical, peripheral venous Duplex and tricuspid Doppler (early diastolic inflow E-wave, late diastolic inflow A-wave, ratios of E to A waves, early diastolic annular e'-wave, late diastolic annular a'-wave and systolic annular s'- wave) data of 85 patients, 133 legs with primary varicose veins. We found following significant (p-value < 0.05) associations between tricuspid Doppler and clinical presentation of chronic venous disease and primary varicose veins: Clinical Etiological Anatomical Pathophysiological clinical class influenced late diastolic inflow velocities (C6 class A-wave +11.2 cm/s or +27% in comparison with C2), late diastolic annular velocities (C6 class a'-wave +3.3 cm/s or +22% in comparison with C2), systolic annular velocities (C6 class s'-wave +3.7 cm/s or +27% in comparison with C2) and E/A ratios (C6 class E/A ratio -0.22 or -21% in comparison with C2). Recurrent varices in comparison with previously untreated are associated with significantly lower late diastolic inflow velocities (A-wave -4.4 cm/s or -9%) and preserved E/A ratios. Age significantly influenced tricuspid Doppler (E-, A-, e'-, a'-waves and E/A ratios) in patients with chronic venous disease. Clinical presentation of primary varicose veins and chronic venous disease can be associated with the right heart diastolic function: C6 Clinical Etiological Anatomical Pathophysiological class in comparison with C2 is associated with increased right ventricular filling and impaired ventricular relaxation - right heart diastolic dysfunction; recurrent varices in comparison with previously untreated are associated with reduced right ventricular filling and preserved right heart diastolic function. Older age is the most important risk factor for varicose veins and chronic venous disease possible due to significant changes in right ventricular filling and in right heart diastolic function with age.

Titin Truncation Position Determines Propensity for Dilated Cardiomyopathy, Impaired Ventricular Relaxation and Passive Stiffness in Zebrafish

Background: Mutations that truncate the giant sarcomeric protein titin are often associated with dilated cardiomyopathy (DCM) but can be non-penetrant. To investigate the basis for this variability, we studied the effects of titin truncation position on cardiac structure and function in adult zebrafish.

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat.

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.

Mitoxantrone-Induced Cardiotoxicity in Acute Myeloid Leukemia-A Velocity Vector Imaging Analysis.

The purpose of this investigation was to: (1) determine incidence and predictors of mitoxantrone-induced early cardiotoxicity and (2) study left ventricular mechanics before and after receiving mitoxantrone. We retrospectively analyzed 80 subjects diagnosed with acute myeloid leukemia (AML) who underwent chemotherapy with bolus high-dose mitoxantrone. Echocardiographic measurements were taken at baseline and at a median interval of 55 days after receiving mitoxantrone. Thirty-five (44%) of the patients developed clinically defined early cardiotoxicity, 29 (36%) of which developed heart failure. There was a significant decrease in the ejection fraction (EF) not only in the cardiotoxicity group (17.6 ± 14.8%, P < 0.001) but also in the noncardiotoxicity group (5.3 ± 8.4%, P < 0.001). Decrease in global longitudinal strain (GLS) (-3.7 ± 4.5, P < 0.001 vs. -2.4 ± 4.3, P = 0.01) and global circumferential strain (GCS) (-5.6 ± 9, P = 0.003 vs. -5.3 ± 8.7, P < 0.001) was significant in both the cardiotoxicity and noncardiotoxicity group, respectively. A multivariate model including baseline left ventricular end-systolic diameter, baseline pre-E/A ratio, and baseline pre-E/e' ratio was found to be the best-fitted model for prediction of mitoxantrone-induced early clinical cardiotoxicity. High-dose mitoxantrone therapy is associated with an excellent remission rate but with a significantly increased risk of clinical and subclinical early cardiotoxicity and heart failure. Mitoxantrone-induced systolic dysfunction is evident from reduction in EF, increase in Tei index, and significant reduction in GLS and GCS. Baseline impaired ventricular relaxation evident from higher E/e' ratio and lower E/A ratio independently predicts increased risk of mitoxantrone-induced early cardiotoxicity.

Increased Transforming Growth Factor-β Levels Associated With Cardiac Adverse Events in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease characterized by ventricular hypertrophy, myocardial fibrosis, and impaired ventricular relaxation. The exact mechanisms by which fibrosis is caused remain unknown. Circulating TGF-β is related to poor prognosis in HCM. We compared TGF-β levels of 49 HCM patients with those of 40 non-HCM patients. We followed the patients with HCM for 18 months and divided them into 2 groups: low TGF-β (≤ 4877 pg/mL) and high TGF-β (> 4877 pg/mL). We compared the 2 groups in terms of brain natriuretic peptide (BNP), echocardiographic parameters, and clinical outcomes including myocardial infarction, arrhythmias, implantable cardioverter-defibrillator implantation, hospitalization, New York Heart Association (NYHA) class, acute heart failure, and mortality. The HCM patients had higher TGF-β levels than those in the control group (P = 0.005). In the follow-up, those in the high TGF-β group had higher BNP levels, larger left-atrial size, thicker interventricular septum, NYHA class, more hospitalizations, and a greater number of clinical adverse events (P < 0.001, P = 0.01, P < 0.001, P = 0.002, P < 0.001 and P = 0.003, respectively). TGF-β level of > 4877 pg/mL can predict adverse events with a specificity of 75% and a sensitivity of 72% (P = 0.014). In multivariate regression analysis, TGF-β, BNP, and interventricular septum thickness were significantly associated with adverse events (P = 0.028, P = 0.030, and P = 0.034, respectively). The TGF-β level is higher in HCM patients and associated with a poor prognosis in HCM.

Changes in Global and Regional Mechanics Due to Atrial Fibrillation: Insights from a Coupled Finite-Element and Circulation Model.

Atrial fibrillation (AF) is a rhythm disorder with rapidly increasing prevalence due to the aging of the population. AF triggers structural remodeling and a gradual loss of function; however, the relative contributions of specific features of AF-induced remodeling to changes in atrial mechanical function are unclear. We constructed and validated a finite-element model (FEM) of the normal human left atrium using anatomic information from cardiac magnetic resonance imaging, material properties and fiber orientations from published studies, and an iterative algorithm to estimate unloaded geometry. We coupled the FEM to a circuit model to capture hemodynamic interactions between the atrium, pulmonary circulation, and left ventricle. The normal model reproduced measured volumes within 1 SD, as well as most metrics of regional mechanics. Using this validated human model as a starting point, we explored the impact of individual features of atrial remodeling on atrial mechanics and found that a combination of dilation, increased pressure, and fibrosis can explain most of the observed changes in mechanics in patients with paroxysmal AF. However, only impaired ventricular relaxation could reproduce the increased reliance on active emptying we observed in these patients. The resulting model provides new insight into the mechanics of AF and a platform for exploring future therapies.

Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system.

BackgroundWe have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.MethodsIR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT1) were assessed by immunofluorescence.ResultsIR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT1 receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.ConclusionsXO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

(848) - Importance of Genetic Evaluation in Pediatric Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is characterized by severely impaired ventricular relaxation with normal or near-normal systolic function and wall thickness. Etiologies of pediatric RCM are poorly understood, however sarcomeric and cytoskeletal mutations have been implicated in prior small studies. We sought to review the yield of commercially available genetic testing in children with RCM at our center.