Ubiquitin Pathway Is Associated with Worsening Left Ventricle Function after Mitral Valve Repair: A Global Gene Expression Study.
ABSTRACT: The molecular mechanism for worsening left ventricular (LV) function after mitral valve (MV) repair for chronic mitral regurgitation remains unknown. We wished to assess the LV transcriptome and identify determinants associated with worsening LV function post-MV repair. A total of 13 patients who underwent MV repair for chronic primary mitral regurgitation were divided into two groups, preserved LV function (N = 8) and worsening LV function (N = 5), for the study. Specimens of LV from the patients taken during surgery were used for the gene microarray study. Cardiomyocyte cell line HL-1 cells were transfected with gene-containing plasmids and further evaluated for mRNA and protein expression, apoptosis, and contractile protein degradation. Of 67,258 expressed sequence tags, microarrays identified 718 genes to be differentially expressed between preserved-LVF and worsening-LVF, including genes related to the protein ubiquitination pathway, bone morphogenetic protein (BMP) receptors, and regulation of eIF4 and p70S6K signaling. In addition, worsening-LVF was associated with altered expressions of genes pathologically relevant to heart failure, such asdownregulated apelin receptors and upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). HL-1 cardiomyocyte cells transfected with ubiquitination-related genes demonstrated activation of the protein ubiquitination pathwaywith an increase in the ubiquitin activating enzyme E1 (UAE-E1). It also led to increased apoptosis, downregulated and ubiquitinated X-linked inhibitor of apoptosis protein (XIAP), and reduced cell viability. Overexpression of ubiquitination-related genes also resulted in degradation and increased ubiquitination of ?-smooth muscle actin (SMA). In conclusion, worsening-LVF presented differential gene expression profiles from preserved-LVF after MV repair. Upregulation of protein ubiquitination-related genes associated with worsening-LVF after MV repair may exert adverse effects on LV through increased apoptosis and contractile protein degradation.
Project description:The extent of mitral annular (MA) remodeling and dysfunction is correlated with the severity of mitral regurgitation (MR) as well as left atrial (LA) and left ventricular (LV) dilation. MA dysfunction may be a useful prognostic factor for operative timing and MR recurrence after successful mitral valve (MV) repair. The aim of this study was to evaluate additive prognostic factors of MA non-planarity using real-time 3D transesophageal echocardiography (RT3D-TEE) analysis in patients with chronic severe MR and preserved LV systolic function.Forty-seven patients with chronic severe MR and preserved LV systolic function scheduled for MV repair were prospectively enrolled. Echocardiographic studies were performed before surgery and postoperatively within 2 weeks and at least 6 months after surgery. RT3D-TEE was performed before the operation and immediately post-operative.Mean age was 55.4 ± 15.1 years and 24 were male. Annulus height/body surface area (BSA) obtained via RT3D-TEE was correlated with the degree of postoperative LA remodeling. Patients were divided into two groups by average baseline annulus height/BSA. Patients with normal annular height had a smaller postoperative LV end-diastolic dimension, LV end-systolic dimension and LA volume index than patients with decreased annular height. Preoperative annulus height/BSA values strongly predicted postoperative LA remodeling.MA height may be a useful prognostic factor for determining the timing of surgery in patients with chronic primary MR. Annulus height/BSA assessed via RT3D-TEE may provide additional information predictive of postoperative LA remodeling after successful MV repair.
Project description:OBJECTIVE:The relationship of mitral annular (MA) kinetics to left ventricular (LV) and left atrial (LA) function before and after mitral valve (MV) repair has not been well studied. Here we sought to provide comprehensive analysis that relates to MA motions, and LA and LV diastolic function post MV repair. METHODS:Three-dimensional analyses of mitral annular motion, LA function, and LV volumetric and diastolic strain rates were performed on 35 degenerative mitral regurgitation (MR) patients at baseline and 1-year post MV repair, and 51 normal controls, utilizing cardiac magnetic resonance imaging with tissue tagging. RESULTS:All had normal LV ejection fraction (EF) at baseline. LV and LA EFs decreased 1-year post-surgery vs. controls. LV early diastolic myocardial strain rates decreased post-surgery along with decreases in normalized early diastolic filling rate, E/A ratio, and early diastolic MA relaxation rates. Post-surgical LA late active kick remained higher in MR patients vs. control. LV and LA EFs were significantly associated with peak MA centroid to apex shortening. Furthermore, during LV systolic phase, peak LV ejection and LA filling rates were significantly correlated with peak MA centroid to apex shortening rate, respectively. While during LV diastolic phase, both peak early diastolic MA centroid to apex relaxation rate and LA ejection rate were positively significantly associated with LV peak early diastolic filling rate. CONCLUSION:MA motion is significantly associated with LA and LV function. Mitral annular motion, left atrial function, and LV diastolic strain rates are still impaired 1?year post MV repair. Long-term effects of these impairments should be prospectively evaluated.
Project description:OBJECTIVES:This study investigated sex-based differences in outcomes after mitral valve (MV) surgery for severe ischemic mitral regurgitation (SIMR). BACKGROUND:Whether differences in outcomes exist between men and women after surgery for SIMR remains unknown. METHODS:Patients enrolled in a randomized trial comparing MV replacement versus MV repair for SIMR were included and followed for 2 years. Endpoints for this analysis included all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE) (defined as the composite of death, stroke, hospitalization for heart failure, worsening New York Heart Association functional class or MV re-operation), quality of life (QOL), functional status, and percentage of change in left ventricular end-systolic volume index (LVESVI) from baseline through 2 years. RESULTS:Of 251 patients enrolled in the trial, 96 (38.2%) were women. Compared with men, women had smaller LV volumes and effective regurgitant orifice areas (EROA) but greater EROA/left ventricular (LV) end-diastolic volume ratios. At 2 years, women had higher rates of all-cause mortality (27.1% vs. 17.4%, respectively; adjusted hazard ratio [adjHR]: 1.85; 95% confidence interval [CI]: 1.05 to 3.26; p = 0.03) and of MACCE (49.0% vs. 38.1%, respectively; adjHR: 1.58; 95% CI: 1.06 to 2.37; p = 0.02). Women also reported worse QOL and functional status at 2 years. There were no significant differences in the percentage of change over 2 years in LVESVI between women and men (adj?: -10.4; 95% CI: -23.4 to 2.6; p = 0.12). CONCLUSIONS:Women with SIMR displayed different echocardiographic features and experienced higher mortality and worse QOL after MV surgery than men. There were no significant differences in the degree of reverse LV remodeling between sexes. (Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation [Severe Ischemic Mitral Regurgitation]; NCT00807040).
Project description:BACKGROUND:In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. METHODS:Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size). RESULTS:At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05-4.62; P=0.038) remained significantly associated with 1-year MR recurrence. CONCLUSIONS:LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone. CLINICAL TRIAL REGISTRATION:URL:http://clinicaltrials.gov. Unique identifiers: NCT00806988 and NCT00807040.
Project description:Background:Appropriate surgical management of moderate functional mitral regurgitation (MR) at the time of coronary artery bypass graft (CABG) surgery remains controversial. A recent study demonstrated no survival benefit from adding mitral repair to CABG for patients with moderate functional MR. Preoperative prediction of reverse remodelling is crucial in making the decision to add mitral valve repair to CABG. Late gadolinium-enhanced magnetic resonance imaging (LGE MRI) offers a reference method to assess myocardial viability. Case summary:A 60-year-old man with ischaemic cardiomyopathy was admitted to our hospital with exacerbation of heart failure symptoms. Left ventricular (LV) dilatation, severe impairment of LV systolic function, and moderate MR due to tethering were noted on transthoracic echocardiography. The mitral regurgitant jet was central. Intravenous administration of furosemide and human atrial natriuretic peptide was initiated. The patient experienced an episode of ventricular tachycardia, and coronary angiography demonstrated triple-vessel disease. On LGE MRI, subendocardial infarction with a transmural extent of 25-50% was revealed in the inferior, posterior, and lateral walls. Findings from LGE MRI suggested that myocardial viability had been preserved. After performing CABG and cardiac resynchronization therapy, LV volume was substantially decreased and moderate MR was significantly improved without surgical mitral repair. On speckle tracking echocardiography before surgery, a significant difference in the times to peak radial strain between the lateral wall (462 ms) and inferior wall (17 ms) indicated the presence of LV dyssynchrony. Left ventricular dyssynchrony was substantially improved after CABG and cardiac resynchronization therapy defibrillator implantation. Discussion:In patients with ischaemic cardiomyopathy and moderate functional MR, acquisition of LGE MRI of the LV should be considered to evaluate the viability of LV myocardium. Findings from LGE MRI of the LV can potentially influence the surgical strategy. In patients with preserved viability of LV myocardium, functional MR could be improved after CABG without any surgical repair.
Project description:OBJECTIVES:Functional mitral regurgitation (FMR) is a significant complication of left ventricle (LV) dysfunction associated with poor prognosis and commonly treated by undersized ring annuloplasty. This study aimed to quantitatively simulate the treatment outcomes and mitral valve (MV) biomechanics following ring annulopalsty and papillary muscle relocation (PMR) procedures for a FMR patient. METHODS:We utilized a validated finite element model of the left heart for a patient with severe FMR and LV dilation from our previous study and simulated virtual ring annuloplasty procedures with various sizes of Edwards Classic and GeoForm annuloplasty rings. The model included detailed geometries of the left ventricle, mitral valve, and chordae tendineae, and incorporated age- and gender- matched nonlinear, anisotropic hyperelastic tissue material properties, and simulated chordal tethering at diastole due to LV dilation. RESULTS:Ring annuloplasty with either the Classic or GeoForm ring improved leaflet coaptation and increased the total leaflet closing force while increased posterior mitral leaflet (PML) stresses and strains. Classic rings resulted in larger coaptation forces and areas compared to GeoForm rings. The PMR procedure further improved the leaflet coaptation, decreased the PML stress and strain for both ring shapes and all sizes in this patient model. CONCLUSIONS:This study demonstrated that a rigorously developed patient-specific computational model can provide useful insights into annuloplasty repair techniques for the treatment of FMR patients and could potentially serve as a tool to assist in pre-operative planning for MV repair surgical or interventional procedures.
Project description:Background Progressive cardiac remodeling and worsening myocardial function over time have been proposed as potential mediators of heart failure in obesity. Methods and Results We serially assessed cardiac structure and function in 254 subjects participating in a longitudinal study of obesity. Demographic, clinical, laboratory, and echocardiographic features were determined at baseline and 2-, 6-, and 11-year follow-up. We measured body mass index (BMI) exposure as the area under the curve of the BMI at each of the 4 visits. At enrollment, mean age of the subjects was 47 years, 79% were women, mean BMI was 44 kg/m2, 26% had diabetes mellitus, 48% had hypertension, and 53% had hyperlipidemia. Between baseline and 11 years, BMI increased by 1.1 and 0.3 kg/m2 in men and women, respectively. There were modest increases in left ventricular (LV) end-diastolic volume, LV mass, and left atrial volume, and significant decreases in early/late mitral diastolic flow velocity ratio and E wave deceleration time. However, there were no significant changes in LV ejection fraction or ratio of early mitral diastolic flow velocity/early mitral annular velocity, whereas right ventricular fractional area change increased. Significant predictors of the change in LV mass were male sex, baseline BMI, BMI area under the curve, and change in LV stroke volume, but not smoking, hypertension, or diabetes mellitus. Conclusions In long-standing, persistent severe obesity, there was evidence of cardiac remodeling over a period of 11 years, but no clear worsening of systolic or diastolic function. Measures of remodeling were most strongly related to BMI. The observed changes might predispose to heart failure with preserved ejection fraction, but are not classic for an evolving dilated cardiomyopathy.
Project description:Degenerative mitral valve disease (DMVD) is the most common cardiac disease in dogs. Some signaling pathways have been implicated in DMVD, including the serotonin and TGF-beta pathways. We sought to identify additional molecular and metabolic pathways that contribute to DMVD using transcriptomic and metabolomic studies. RNA-seq gene expression evaluated on total RNA isolated from left ventricle (LV) and mitral valve (MV) identified 812 differentially expressed transcripts (DETs) in LV and 263 DETs in MV. Out of 15 transcripts selected for RT-qPCR validation, we confirmed 13. In addition, serum samples were collected for metabolomic evaluation. Endothelial nitric oxide synthase (eNOS) was significantly up-regulated in both LV and MV while the level of circulating asymmetrical dimethyl arginine (ADMA), an endogenous NOS inhibitor, was lower in DMVD. Expressions of matrix metalloproteinases (MMP) and their endogenous inhibitor tissue inhibitor of matrix metallopeptidases (TIMP) were altered. This study demonstrates transcript and metabolite differences consistent with increased nitric oxide (NO) and reactive oxygen species (ROS) production, impaired fatty acid transport and oxidation, and increased glucose uptake and glycolysis in DMVD. Our findings are consistent with metabolic conversion in the DMVD heart from oxidative metabolism to glycolysis along with an increased concentration of NO and ROS activity suggesting an alternative signaling effect. Alterations of redox-sensitive NO signaling may play a role in ECM (ECM) homeostasis via modulating MMP and TIMP expression. Overall design: mRNA profiles of both left ventricle and mitral valve tissues from dogs with DMVD and healthy controls were generated by deep sequencing approach using Illumina HiSeq 2000 platform.
Project description:Highly resolved three-dimensional (3D) fluid structure interaction (FSI) simulation using patient-specific echocardiographic data can be a powerful tool for accurately and thoroughly elucidating the biomechanics of mitral valve (MV) function and left ventricular (LV) fluid dynamics. We developed and validated a strongly coupled FSI algorithm to fully characterize the LV flow field during diastolic MV opening under physiologic conditions. Our model revealed that distinct MV deformation and LV flow patterns developed during different diastolic stages. A vortex ring that strongly depended on MV deformation formed during early diastole. At peak E wave, the MV fully opened, with a local Reynolds number of ~5500, indicating that the flow was in the laminar-turbulent transitional regime. Our results showed that during diastasis, the vortex structures caused the MV leaflets to converge, thus increasing mitral jet's velocity. The vortex ring became asymmetrical, with the vortex structures on the anterior side being larger than on the posterior side. During the late diastolic stages, the flow structures advected toward the LV outflow tract, enhancing fluid transport to the aorta. This 3D-FSI study demonstrated the importance of leaflet dynamics, their effect on the vortex ring, and their influence on MV function and fluid transport within the LV during diastole.
Project description:Because of demographic changes, a growing number of elderly patients present with mitral valve (MV) disease. Although mitral valve repair (MV-repair) is the "gold standard" treatment for MV disease, in elderly patients, there is controversy about whether MV-repair is superior to mitral valve replacement. We reviewed results after MV surgery in elderly patients treated over the past 20 years.Our in-hospital database was explored for patients who underwent MV surgery between 1994 and 2015. Survival data, obtained from the National Health Service central register, were complete for all patients. Of 1776 patients with MV disease, 341 were aged ?75 years. Patients with repeat cardiac surgery, endocarditis, and concomitant aortic valve replacement were excluded. This yielded 221 MV-repair and 120 mitral valve replacement patients. Concomitant procedures included coronary artery bypass grafting in 135 patients (39.6%) and tricuspid valve surgery in 50 patients (14.7%). Thirty-day mortality was 5.4% (MV-repair) versus 9.2% (mitral valve replacement, P=0.26). Overall 1- and 5-year survival was 90.7%, 74.2% versus 81.3%, 61.0% (P<0.01). Median survival after MV-repair was 7.8 years, close to 8.5 years (95% CI: 8.2-9.4) in the age-matched UK population (ratio 0.9). Rate of re-operation for MV-dysfunction was 2.3% versus 2.5% (mitral valve replacement, P=1.0). After propensity matching, patients after MV-repair still had improved survival at 1, 2, and 5 years (93.4%, 91.6%, 76.9% versus 77.2%, 75.2%, 58.7%, P=0.03).Excellent outcomes can be achieved after MV surgery in elderly patients. Long-term survival is superior after MV-repair and the re-operation rate is low. MV-repair should be the preferred surgical approach in elderly patients.