Previous studies have demonstrated the feasibility of producing fatty-acid-derived hydrocarbons in Escherichia coli. However, product titers and yields remain low. In this work, we demonstrate new methods for improving fatty acid production by modifying central carbon metabolism and storing fatty acids in triacylglycerol. Based on suggestions from a computational model, we deleted seven genes involved in aerobic respiration, mixed-acid fermentation, and glyoxylate bypass (in the order of cyoA, nuoA, ndh, adhE, dld, pta, and iclR) to modify the central carbon metabolic/regulatory networks. These gene deletions led to increased total fatty acids, which were the highest in the mutants containing five or six gene knockouts. Additionally, when two key enzymes in the fatty acid biosynthesis pathway were over-expressed, we observed further increase in strain △cyoA△adhE△nuoA△ndh△pta△dld, leading to 202 mg/g dry cell weight of total fatty acids, ~250% of that in the wild-type strain. Meanwhile, we successfully introduced a triacylglycerol biosynthesis pathway into E. coli through heterologous expression of wax ester synthase/acyl-coenzyme:diacylglycerol acyltransferase (WS/DGAT) enzymes. The added pathway improved both the amount and fuel quality of the fatty acids. These new metabolic engineering strategies are providing promising directions for future investigation.
We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.
Methods and results
Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype.
These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
Filamin-A; Serotonin; Myxomatous valve disease; Transglutaminase-2; Valve maturation
In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3–cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group.
GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.
Atrioventricular valve development commences with an EMT event whereby endocardial cells transform into mesenchyme. The molecular events that induce this phenotypic change are well understood and include many growth factors, signaling components, and transcription factors. Besides their clear importance in valve development, the role of these transformed mesenchyme and the function they serve in the developing prevalve leaflets is less understood. Indeed, we know that these cells migrate, but how and why do they migrate? We also know that they undergo a transition to a mature, committed cell, largely defined as an interstitial fibroblast due to their ability to secrete various matrix components including collagen type I. However, we have yet to uncover mechanisms by which the matrix is synthesized, how it is secreted, and how it is organized. As valve disease is largely characterized by altered cell number, cell activation, and matrix disorganization, answering questions of how the valves are built will likely provide us with information of real clinical relevance. Although expression profiling and descriptive or correlative analyses are insightful, to advance the field, we must now move past the simplicity of these assays and ask fundamental, mechanistic based questions aimed at understanding how valves are ‘built”. Herein we review current understandings of atrioventricular valve development and present what is known and what isn’t known. In most cases, basic, biological questions and hypotheses that were presented decades ago on valve development still are yet to be answered but likely hold keys to uncovering new discoveries with relevance to both embryonic development and the developmental basis of adult heart valve diseases. Thus, the goal of this review is to remind us of these questions and provide new perspectives on an old theme of valve development.
Valve Development; EMT; Post-EMT; Valve Disease; cushions; Fibroblasts
Standard written methods of presenting research information may be difficult for many parents and children to understand. This pilot study was designed to examine the use of a novel prototype interactive consent program for describing a hypothetical pediatric asthma trial to parents and children. Parents and children were interviewed to examine their baseline understanding of key elements of a clinical trial, eg, randomization, placebo, and blinding. Subjects then reviewed age-appropriate versions of an interactive computer program describing an asthma trial, and their understanding of key research concepts was again tested along with their understanding of the details of the trial. Parents and children also completed surveys to examine their perceptions and satisfaction with the program. Both parents and children demonstrated improved understanding of key research concepts following administration of the consent program. For example, the percentage of parents and children who could correctly define the terms clinical trials and placebo improved from 60% to 80%, and 80% to 100% among parents and 25% to 50% and 0% to 50% among children, respectively, following review of the interactive programs. Parents and children's overall understanding of the details of the asthma trial were 14.2±0.84 and 9.25±4.9 (0–15 scale, where 15 is complete understanding), respectively. Results also suggest that the interactive programs were easy to use and facilitated understanding of the clinical trial among parents and children. Interactive media may offer an effective means of presenting understandable information to parents and children regarding participation in clinical trials. Further work to examine this novel approach appears warranted.
To test the hypothesis that mitral valve (MV) enlargement occurring in chronic aortic regurgitation (AR) prevents functional mitral regurgitation (FMR).
Chronic AR causes left ventricular (LV) dilatation, creating the potential for FMR. However, FMR is typically absent during compensated AR despite substantial LV enlargement. Increased mitral leaflet area has been identified in AR, but it is unknown whether increased MV size can represent a compensatory mechanism capable of preventing FMR.
Database review of 816 patients with at least moderate AR evaluated the prevalence of FMR. A total of 90 patients were enrolled prospectively for 3D echocardiography (30 AR, 30 FMR and 30 controls) to assess MV geometry including total leaflet area.
FMR was present in 5.6% of AR patients by database review. Prospectively, only one AR patient had >mild FMR despite increased LV end-diastolic volume (82±22, 86±23 and 51±12 cm3/m2 for AR, FMR versus controls, p<0.01), and similar sphericity index, annular area and tethering distances compared to FMR. Total MV area was largest in AR (31.3% greater than normal), increasing significantly more than in FMR. The ratio of valve size to closure area was maintained in AR while decreases in this ratio and LVEF independently predicted FMR.
FMR prevalence is low in chronic AR. MV leaflet area is significantly increased compared to controls and FMR patients, preserving a normal relation to the area needed for closure in the dilated LV. Understanding the mechanisms underlying this adaptation could lead to new therapeutic interventions to prevent FMR.
Aortic regurgitation; functional mitral regurgitation; valvular disease
Thanks to integrative physiology, new relationships between organs and homeostatic functions have emerged. This approach to physiology based on a whole organism approach has allowed the bone field to make fundamental progress.
In the last decade, clinical observations and scientific evidences in vivo have uncovered that fat with leptin controls bone mass through brain including a hypothalamic relay and sympathetic nervous system.
The finding that energy metabolism affects bone remodelling suggested that in an endocrine perspective, a feedback loop should exist. Beside its classical functions, bone can now be considered as a true endocrine organ secreting osteocalcin, a hormone pharmacologically active on glucose and fat metabolism. Indeed osteocalcin stimulates insulin secretion and β-cell proliferation. Simultaneously, osteocalcin acts on adipocytes to induce Adiponectin which secondarily reduce insulin resistance. This cross regulation between bone and energy metabolism offers novel therapeutic targets in type 2 diabetes and osteoporosis.
Bone; osteocalcin; leptin; SNS; energy metabolism
Mitral regurgitation (MR) has been associated with adverse outcomes after myocardial infarction (MI). Without structural valve disease, functional MR has been related to left ventricular (LV) remodeling and geometric deformation of the mitral apparatus. The aims of this study were to elucidate the mechanistic components of MR after high-risk MI and to identify predictors of MR progression during follow-up.
The Valsartan in Acute Myocardial Infarction Echo substudy prospectively enrolled 610 patients with LV dysfunction, heart failure, or both after MI. MR at baseline, 1 month, and 20 months was quantified by mapping jet expansion in the left atrium in 341 patients with good-quality echocardiograms. Indices of LV remodeling, left atrial size, and diastolic function and parameters of mitral valve deformation, including tenting area, coaptation depth, anterior leaflet concavity, annular diameters, and contractility, were assessed and related to baseline MR. The progression of MR was further analyzed, and predictors of worsening among the baseline characteristics were identified.
Tenting area, coaptation depth, annular dilatation, and left atrial size were all associated with the degree of baseline MR. Tenting area was the only significant and independent predictor of worsening MR; a tenting area of 4 cm2 was a useful cutoff to identify worsening of MR after MI and moderate to severe MR after 20 months.
Increased mitral tenting and larger mitral annular area are determinants of MR degree at baseline, and tenting area is an independent predictor of progression of MR after MI. Although LV remodeling itself contributes to ischemic MR, this influence is directly dependent on alterations in mitral geometry.
Mitral regurgitation; Myocardial infarction; Mitral geometry; Tenting area; Left ventricular remodeling
U.S. health disparities are real, pervasive, and persistent, despite dramatic improvements in civil rights and economic opportunity for racial and ethnic minority and lower socioeconomic groups in the United States. Change is possible, however. Disparities vary widely from one community to another, suggesting that they are not inevitable. Some communities even show paradoxically good outcomes and relative health equity despite significant social inequities. A few communities have even improved from high disparities to more equitable and optimal health outcomes. These positive-deviance communities show that disparities can be overcome and that health equity is achievable. Research must shift from defining the problem (including causes and risk factors) to testing effective interventions, informed by the natural experiments of what has worked in communities that are already moving toward health equity. At the local level, we need multi-dimensional interventions designed in partnership with communities and continuously improved by rapid-cycle surveillance feedback loops of community-level disparities metrics. Similarly coordinated strategies are needed at state and national levels to take success to scale. We propose ten specific steps to follow on a health equity path toward optimal and equitable health outcomes for all Americans.
Health equity; disparities; public health; primary care; success; health outcomes; race
Objective. This analysis focuses on the effect of depression on the cost of hospitalization of stroke patients. Methods. Data on 17,010 stroke patients (primary diagnosis) were extracted from 2008 Tennessee Hospital Discharge Data System. Three groups of patients were compared: (1) stroke only (SO, n = 7,850), (2) stroke + depression (S+D, n = 3,965), and (3) stroke + other mental health diagnoses (S+M, n = 5,195). Results. Of all adult patients, 4.3% were diagnosed with stroke. Stroke was more prevalent among blacks than whites (4.5% versus 4.2%, P < 0.001) and among males than females (5.1% versus 3.7%, P < 0.001). Nearly one-quarter of stroke patients (23.3%) were diagnosed with depression/anxiety. Hospital stroke cost was higher among depressed stroke patients (S+D) compared to stroke only (SO) patients ($77,864 versus $47,790, P < 0.001), and among S+D, cost was higher for black males compared to white depressed males ($97,196 versus $88,115, P < 0.001). Similar racial trends in cost emerged among S+D females. Conclusion. Depression in stroke patients is associated with increased hospitalization costs. Higher stroke cost among blacks may reflect the impact of comorbidities and the delay in care of serious health conditions. Attention to early detection of depression in stroke patients might reduce inpatient healthcare costs.
Introduction. Motor vehicle crashes are the leading cause of death among US children aged 4–14 years. In theory, health provider counseling about Child Passenger Safety (CPS) could be a useful deterrent. The data about the effectiveness of CPS dissemination is sparse, but existing results suggest that providers are not well informed. Moreover, there is insufficient evidence to determine whether provider counseling about CPS is effective. Methods. We therefore assessed CPS best practice knowledge among 217 healthcare workers at hospitals in seven cities throughout the USA and evaluated the impact of a brief, lunch and learn educational intervention with a five-item questionnaire. Attendees were comprised of physicians, nurses, social workers, pediatric residents, and pediatric trauma response teams. Results. Pre-post survey completion was nearly 100% (216 of 217 attendees). Participation was fairly evenly distributed according to age (18–29, 30–44, and 45+ years). More than 80% of attendees were women. Before intervention, only 4% of respondents (9/216) answered all five questions correctly; this rose to 77% (167/216) (P < 0.001, using a Wilcoxon signed-rank test) after intervention. Conclusion. Future research should consider implementation and controlled testing of comparable educational programs to determine if they improve dissemination of CPS best practice recommendations in the long term.
The uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of osteocalcin. We found that daily injections of osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both β-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving osteocalcin daily. Overall, these results provide evidence that daily injections of osteocalcin can improve glucose handling and prevent the development of type 2 diabetes.
Glucose; Insulin; Osteocalcin; High fat diet; Energy expenditure; Liver steatosis
Homicide is seven times as common among U.S. non-Hispanic Black as among non-Hispanic White youth ages 15 to 24 years. In 83% of these youth homicides, the murder weapon is a firearm. Yet, for more than a decade, the national public health position on youth violence has been largely silent about the role of firearms, and tools used by public health professionals to reduce harm from other potential hazards have been unusable where guns are concerned. This deprives already underserved populations from the full benefits public health agencies might be able to deliver. In part, political prohibitions against research about direct measures of firearm control and the absence of valid public health surveillance are responsible. More refined epidemiologic theories as well as traditional public health methods are needed if the U.S. aims to reduce disparate Black-White youth homicide rates.
Firearms; African Americans; public health; conflict of interest
There is uncertainty and debate regarding whether ischemic mitral regurgitation (MR) is a secondary epiphenomenon resulting from left ventricular (LV) dysfunction or confers an independent effect on exercise capacity and outcomes. We tested whether ischemic MR negatively impacts exercise capacity, cardiovascular morbidity and mortality in patients with coronary artery disease (CAD) and inferior wall motion abnormality patients, independent of LV dysfunction. Clinical follow-up over 5 years was obtained in 77 patients (age 64±10 years, LVEF 54±11%) with at least mild ischemic MR from CAD and evidence of inferior wall motion abnormality, who had exercise stress testing with perfusion imaging within 24 hours of echocardiography. Patients with active heart failure, ischemia, intrinsic valve disease, pulmonary and vascular disease were excluded. Exercise capacity (METs, peak double product) was tested for relation to MR (vena contracta (VC) and jet area), LV size and function, and pulmonary pressures. Cox proportional hazards analysis assessed whether MR predicted cardiovascular events, including hospitalization for heart failure, acute coronary syndrome, and myocardial infarction, and cardiovascular (CV) and total mortality. Univariate correlation identified MR with both VC (r=−0.674, p<0.0001) and MR jet area (r=−0.575, p<0.0001) as determinants of reduced functional capacity evaluated by METs, with VC the stronger predictor. MR VC > 2 mm (moderate ischemic MR) and age were independent predictors of CV events and death (HR 6.72 for MR, p=0.04). In conclusion, in patients with CAD and LV inferior wall motion abnormality, MR impacts negatively on exercise capacity and is associated with increased cardiovascular morbidity and mortality. This effect appears independent of degree of LV dysfunction.
exercise capacity; ischemic mitral regurgitation
Mitral valve prolapse; animal study; biomechanics; chordal tension
Background and aim of the study
Ischemic mitral regurgitation often persists despite annular ring reduction. We hypothesized that persistent ischemic mitral regurgitation following ring annuloplasty relates to continued tethering of the mitral leaflets as defined by displaced papillary muscles distance outside of the mitral annular ring.
Materials & methods
7 sheep (4 acute and 3 chronic) with persistent mitral regurgitation following ring annuloplasty for ischemic mitral regurgitation were studied by 3D echocardiography to examine mitral valve geometry. Three stages were examined: Stage 1-baseline, Stage 2-post myocardial infarction (via ligation of obtuse marginal branches) and Stage 3-post undersized ring annuloplasty. Three-dimensional echocardiography measurements included: mitral annular area, tethering distance from the ischemic papillary muscle to anterior annulus, and outside displacement of papillary muscle relative to ring papillary muscle displacement.
Persistent moderate MR remained in these seven sheep following undersized ring (MR vena contracta change: 7 vs 5.8 ± 2.4 mm; pre vs post ring, p=ns) despite a reduction in mitral annular area of 50±18% (10.3±6.3 vs. 4.7±1.3 cm2). Ring annuloplasty shifted the posterior annulus toward the anterior annulus such that the infarcted papillary muscle became displaced outside the mitral annulus. The projected displacement distance of PM outside versus inside annular ring was 8.4±2.4 mm outside mitral annulus-post ring vs. 3.6±2.5 mm within mitral annulus-pre ring, p<0001). The displacement distance from the infarcted papillary muscle to the mitral annulus, restricted the ability of the posterior leaflet to move anteriorly, preventing effective coaptation. By multivariate analysis, this displacement distance was an important determinant of residual mitral regurgitation (p<0.02).
Persistent mitral regurgitation following ring annuloplasty for ischemic mitral regurgitation relates to persistently abnormal leaflet tethering, with restricted posterior leaflet motion due to papillary muscle displacement outside of the mitral annulus.
mitral regurgitation; valve repair
The mitral valve annulus naturally conforms to a saddle shape in systole. This configuration is believed to put the leaflets into a lower-energy equilibrium with the annulus and subvalvular apparatus. Conventional flat annuloplasty rings restrict posterior leaflet motion, which may result in a “monocusp” valve, affecting valvular stress distribution. It is hypothesized that saddle-shaped annuloplasty rings cause less distortion of the physiologic leaflet geometry than do flat rings.
Twelve pigs were studied in an acute setting with 3-dimensional echocardiography and sonomicrometry before and after implantation of rigid flat (n = 5) and saddle-shaped (n = 7) annuloplasty rings. The rings were true sized to the annulus with equal anterior–posterior and commissure–commissure circumferential dimensions. The saddle-shaped rings had an annular height to commissural width ratio of 15%.
Saddle-shaped rings maintained both leaflets operational (P <.01). Flat rings made the posterior leaflet immobile and the anterior leaflet aligned flat along the annulus in systole, effectively resulting in monoleaflet function. The average distance from the papillary muscle tips to the posterior annulus decreased by 2.4 ± 0.4 mm after flat ring implantation (P <.01).
Saddle-shaped annuloplasty rings provide better leaflet coaptation geometry than do flat rings by not hoisting the papillary muscles toward the posterior annulus through the commissural chordae, allowing greater leaflet mobility. This entails a potentially beneficial impact on valvular stress distribution that could affect durability of the repaired valve.
Accurate quantification of mitral regurgitation (MR) is important for patient treatment and prognosis. Three-dimensional echocardiography allows for the direct measure of the regurgitant orifice area (ROA) by 3D-guided planimetry of the vena contracta area (VCA). We aimed to (1) establish 3D VCA ranges and cutoff values for MR grading, using the American Society of Echocardiography–recommended 2D integrative method as a reference, and (2) compare 2D and 3D methods of ROA to establish a common calibration for MR grading.
Methods and Results
Eighty-three patients with at least mild MR underwent 2D and 3D echocardiography. Direct planimetry of VCA was performed by 3D echocardiography. Two-dimensional quantification of MR included 2D ROA by proximal isovelocity surface area (PISA) method, vena contracta width, and ratio of jet area to left atrial area. There were significant differences in 3D VCA among patients with different MR grades. As assessed by receiver operating characteristic analysis, 3D VCA at a best cutoff value of 0.41 cm2 yielded 97% of sensitivity and 82% of specificity to differentiate moderate from severe MR. There was significant difference between 2D ROA and 3D VCA in patients with functional MR, resulting in an underestimation of ROA by 2D PISA method by 27% as compared with 3D VCA. Multivariable regression analysis showed functional MR as etiology was the only predictor of underestimation of ROA by the 2D PISA method.
Three-dimensional VCA provides a single, directly visualized, and reliable measurement of ROA, which classifies MR severity comparable to current clinical practice using the American Society of Echocardiography–recommended 2D integrative method. The 3D VCA method improves accuracy of MR grading compared with the 2D PISA method by eliminating geometric and flow assumptions, allowing for uniform clinical grading cutoffs and ranges that apply regardless of etiology and orifice shape.
mitral regurgitation; diagnosis; 3D echocardiography; Doppler echocardiography
Insulin signaling in osteoblasts contributes to whole-body glucose homeostasis in the mouse and in humans by increasing the activity of osteocalcin. The osteoblast insulin signaling cascade is negatively regulated by ESP, a tyrosine phosphatase dephosphorylating the insulin receptor. Esp is one of many tyrosine phosphatases expressed in osteoblasts, and this observation suggests that other protein tyrosine phosphatases (PTPs) may contribute to the attenuation of insulin receptor phosphorylation in this cell type. In this study, we sought to identify an additional PTP(s) that, like ESP, would function in the osteoblast to regulate insulin signaling and thus affect activity of the insulin-sensitizing hormone osteocalcin. For that purpose, we used as criteria expression in osteoblasts, regulation by isoproterenol, and ability to trap the insulin receptor in a substrate-trapping assay. Here we show that the T-cell protein tyrosine phosphatase (TC-PTP) regulates insulin receptor phosphorylation in the osteoblast, thus compromising bone resorption and bioactivity of osteocalcin. Accordingly, osteoblast-specific deletion of TC-PTP promotes insulin sensitivity in an osteocalcin-dependent manner. This study increases the number of genes involved in the bone regulation of glucose homeostasis.
In this chapter, we review the working hypothesis that the roots of adult valvular heart disease (VHD) lie in embryonic development. Valvulogenesis is a complex process in which growth factors signal the process of endocardium-to-mesenchyme transformation (EMT) resulting in formation of prevalvular “cushions.” The post-EMT processes, whereby cushions are morphogenetically remolded into valve leaflets, are less well understood, but they require periostin. Mice with targeted deletion of periostin develop degenerative changes similar to human forms of VHD. Mitral valves are also abnormally elongated in hypertrophic cardiomyopathy (HCM), which plays an important role in clinical disease expression. However, the mechanism for this is unclear, but correlates with enhanced expression of periostin in a specific population of ventricular cells derived from the embryonic proepicardial organ, which accumulate at sites where valvular endocardial EMT is reactivated. Collectively, these findings suggest that developmental mechanisms underlie adult valve responses to genetic mutations in degenerative VHD and HCM.
valvulogenesis; differentiation; mitral valves; periostin; cardiomyopathy; EMT; stem cells
Mitral regurgitation (MR) generally accompanies infero-basal myocardial infarction (MI), with leaflet tethering by displaced papillary muscles (PMs). MR is also reported with antero-apical MI without global dilatation or inferior wall-motion abnormalities. We hypothesized that anteroapical MI extending to the inferior apex displaces the PMs, tethering the mitral leaflets to cause MR.
Methods and Results
Retrospective study: Consecutive anteroapical MI patients were studied. Moderate-severe MR occurred in 9% of 234 pts with only anteroapical MI versus 17% of 242 with inferoapical extension (p<0.001). EF was only mildly different (41±4% vs 46±5%, p<0.01).
Human mechanistic study: Sixty anteroapical MI patients (20 with only two apical segments involved and 40 with involvement of all 4 apical segments, 20 with MR and 20 without MR), were compared to 20 normal controls. Those with MR (moderate) had higher systolic PM-to-annulus tethering length (TL) (p<0.01). MR grade correlated most strongly with TL (r=0.70) and its diminished systolic shortening (r=−0.65).
Animal study: 9 sheep with LAD ligation were analyzed. Four sheep that developed MR had inferoapical MI extension with TL increasing over 1.5 months (2.1±0.4 to 2.9±0.4 cm, p<0.001), versus no significant increase in 5 sheep without MR (2.0±0.4 to 2.1±0.3 cm, p=NS). In MR sheep, the normal decrease in TL from diastole to systole was eliminated (p<0.01).
Anteroapical MI with inferoapical extension can mechanically displace PMs, causing MR despite the absence of basal and mid-inferior wall motion abnormalities. This suggests the possibility of repositioning treatments for this condition.
Ischemic Mitral Regurgitation; Anterior Myocardial Infarction; 3-Dimensional echocardiography