Showing papers by "Robert A. Levine published in 2015"

Mitral valve disease—morphology and mechanisms

Abstract: Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but--even in adult life--remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Mutations in DCHS1 cause mitral valve prolapse

Abstract: Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Abstract: Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.

Mitral Annular Evaluation With CT in the Context of Transcatheter Mitral Valve Replacement

Abstract: With the advent of transcatheter mitral valve replacement (TMVR) [(1)][1], the assessment of mitral annular dimensions by computed tomography (CT) is of increasing relevance. The nonplanar, saddle-shaped, 3-dimensional structure of the mitral annulus has been well established [(2)][2] with the

Familial Clustering of Mitral Valve Prolapse in the Community

Abstract: Background—Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community using current, more specific echocardiographic criteria is unknown. In addition, the importance of nondiagnostic MVP morphologies (NDMs; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDMs increase the risk of offspring MVP. Methods and Results—Study participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDMs were distinguished by leaflet displacement >2 versus ≤2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least 1 parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age, 40±9 years), 49 (1%) had MVP. Pare...

Leaflet area as a determinant of tricuspid regurgitation severity in patients with pulmonary hypertension.

Abstract: Background— Tricuspid regurgitation (TR) is a risk factor for mortality in pulmonary hypertension (PH). TR severity varies among patients with comparable degrees of PH and right ventricular remodeling. The contribution of leaflet adaptation to the pathophysiology of TR has yet to be examined. We hypothesized that tricuspid leaflet area (TLA) is increased in PH, and that the adequacy of this increase relative to right ventricular remodeling determines TR severity. Methods and Results— A prospective cohort of 255 patients with PH from pre and postcapillary pathogeneses was assembled from 2 centers. Patients underwent a 3-dimensional echocardiogram focused on the tricuspid apparatus. TLA was measured with the Omni 4D software package. Compared with normal controls, patients with PH had a 2-fold increase in right ventricular volumes, 62% increase in annular area, and 49% increase in TLA. Those with severe TR demonstrated inadequate increase in TLA relative to the closure area, such that the ratio of TLA:closure area Conclusions— TLA plays a significant role in determining which patients with PH develop severe functional TR. The ratio of TLA:closure area, reflecting the balance between leaflet adaptation versus annular dilation and tethering forces, is an indicator of TR severity that may identify which patients stand to benefit from leaflet augmentation during tricuspid valve repair.

MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions.

Abstract: Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1-8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP.

The mitral valve is an actively adapting tissue: new imaging evidence

Abstract: With the mitral valve (MV) leaflet bases arising from the mitral annulus (MA) and the leaflet body and tips connected via the chordae and papillary muscles (PM) to the left ventricular (LV) wall, the anterior and posterior MV leaflets are hoisted like sails. The precise systolic spatial and temporal three-dimensional (3D) interplay of all these structures ensures optimal MV leaflet coaptation within the LV cavity just at the level of the MA, while preventing leaflet displacement into the left atrium (LA; prolapse) or the LV outflow tract (systolic anterior motion, SAM). Any change in form or function that leads to an imbalance of this interplay can result in mechanical leaflet stretch, and if leaflet redundancy is exhausted, to a relative leaflet tissue to MA area deficit and therefore mitral regurgitation (MR).1 Gradually evolving changes that do not unsettle this balance, such as fetal to adulthood growth, seem to allow the MV leaflets to adapt, grow and match the needs of the enlarging LV and MA (×20 area increase).2 The …

Efficacy of polymer injection for ischemic mitral regurgitation: persistent reduction of mitral regurgitation and attenuation of left ventricular remodeling.

Abstract: Objectives The aim of this study was to examine the chronic effects of polyvinyl-alcohol (PVA) injection on mitral regurgitation (MR) reduction, mitral valve geometry, and left ventricular (LV) remodeling in a chronic ischemic MR sheep model Background Previous studies have demonstrated acute efficacy of PVA hydrogel polymer injection into infarcted myocardium underlying the papillary muscle to relieve MR by papillary muscle repositioning However, the chronic efficacy of PVA injection in the chronic infarction setting remains unclear Methods Sixteen sheep developed chronic MR 8 weeks after induced inferoposterior myocardial infarction Ten consecutive sheep underwent PVA injection (PVA group) and 6 sheep served as control subjects with saline injection Epicardial 2-/3-dimensional echocardiography was performed at the baseline, chronic MR (pre-injection), and sacrifice (8 weeks after injection) stages Results Both groups were comparable at the baseline and chronic MR stages At sacrifice, MR decreased from moderate to trace or mild (vena contracta: 017 ± 008 cm vs 056 ± 010 cm, p Conclusions Polymer injection in a chronic ischemic MR model results in persistent reduction of MR and attenuation of continued left ventricular remodeling over 8 weeks of follow-up

Dynamic changes of the mitral valve annulus: new look at mitral valve diseases.

Abstract: The appreciation of mitral valve prolapse (MVP) has evolved from clinical recognition1 to surgical classification to guide repair,2 echocardiographic analysis, and specificity3,4 with 3-dimensional (3D) depiction5 and most recently genetic and molecular studies.6,7 Two manifestations of degenerative mitral valve disease (DMVD), the main cause of MVP, have been recognized: diffuse myxomatous degeneration (DMD) with involvement of multiple scallops of both leaflets and fibroelastic deficiency (FED), with generally thin leaflets except for myxoid degeneration of one or a few scallops of a single leaflet, generally the posterior.8 From both mechanistic and surgical perspectives, it remains unresolved whether these are 2 distinct phenotypes or a spectrum, and whether the localized thickening in FED is primary or secondary to the adjacent turbulent blood flow emerging from a scallop with deficient chordal restraint. See Article by Clavel et al Clavel et al,9 in this issue of Circulation: Cardiovascular Imaging , have now contributed information from dynamic quantitative 3D echocardiography relevant to this question in patients undergoing reconstructive surgery that allows visual classification. Despite comparable mitral regurgitation (MR) severity consistent with surgical selection, in addition to previously described static anatomic characteristics, namely enlarged annulus and excess valvular tissue,5 cyclic annular dynamics are blunted in DMD and systolic leaflet area changes are reduced in FED. These findings raise the possibility of primary alterations of the mitral annulus and biomechanical differences in the leaflet tissue,10,11 with excess distensible tissue in DMD versus relatively deficient and less extensible tissue in FED. These variations could reveal differences in mechanism and require differences in surgical approach. DMVD can affect any of the mitral apparatus components: the leaflets, chordae tendineae, papillary muscles, and annulus. Whether …

Different characteristics of heart failure due to pump failure and bradyarrhythmia

Abstract: Background Heart failure (HF) can be caused by left ventricular (LV) pump failure as well as by bradyarrhythmias. Hemodynamic differences between HF by LV pump failure and that by bradyarrhythmia have not been fully investigated. We hypothesized that HF by LV pump failure could be associated with both reduced cardiac output (CO) and increased LV filling pressure due to associated LV diastolic dysfunction, whereas HF by bradyarrhythmia could be associated with reduced CO but only modestly increased LV filling pressure due to the absence of LV diastolic dysfunction.

Targeted Mybpc3 Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities

Abstract: MYBPC3 mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compare Mybpc3-null, heterozygous, and wild-type mice (n = 84, aged 3-6 months) and micro-CT for MV volume (n = 6, age 6 months). Mybpc3-null mice showed left ventricular hypertrophy, dilation, and systolic dysfunction compared to heterozygous and wild-type mice, but no systolic anterior motion of the MV or left ventricular outflow obstruction. Compared to wild-type mice, echocardiographic anterior leaflet length (adjusted for left ventricular size) was greatest in Mybpc3-null mice (1.92 ± 0.08 vs. 1.72 ± 0.08 mm, p < 0.001), as was combined leaflet thickness (0.23 ± 0.04 vs. 0.15 ± 0.02 mm, p < 0.001). Micro-CT analyses of Mybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06 vs. 0.15 ± 0.06 mm3, p = 0.018) and thickness (0.35 ± 0.04 vs. 0.12 ± 0.04 mm, p = 0.002), coincident with increased markers of TGFβ activity compared to heterozygous and wild-type littermates. Similarly, excised MV from a patient with MYBPC3 mutation showed increased TGFβ activity. We conclude that MYBPC3 deficiency causes hypertrophic cardiomyopathy with increased MV leaflet length and thickness despite the absence of left ventricular outflow-tract obstruction, in parallel with increased TGFβ activity. MV changes in hypertrophic cardiomyopathy may be due to paracrine effects, which represent targets for therapeutic studies.

Myocardial perfusion pattern for stratification of ischemic mitral regurgitation response to percutaneous coronary intervention.

Abstract: OBJECTIVE Ischemic mitral regurgitation (MR) is common, but its response to percutaneous coronary intervention (PCI) is poorly understood. This study tested the utility of myocardial perfusion imaging (MPI) for the stratification of MR response to PCI. METHODS MPI and transthoracic echocardiography (echo) were performed among patients undergoing PCI. MPI was used to assess stress/rest myocardial perfusion. MR was assessed via echo (performed before and after PCI). RESULTS A total of 317 patients with abnormal myocardial perfusion on MPI underwent echo 25±39 days before PCI. MR was present in 52%, among whom 24% had advanced (≥moderate) MR. MR was found to be associated with left ventricular (LV) chamber dilation on MPI and echo (both P<0.001). The magnitude of global LV perfusion deficits increased in relation to MR severity (P<0.01). Perfusion differences were greatest for global summed rest scores, which were 1.6-fold higher among patients with advanced MR versus those with mild MR (P=0.004), and 2.4-fold higher versus those without MR (P<0.001). In multivariate analysis, advanced MR was found to be associated with a fixed perfusion defect size on MPI [odds ratio 1.16 per segment (confidence interval 1.002-1.34), P=0.046], independent of LV volume [odds ratio 1.10 per 10 ml (confidence interval 1.04-1.17), P=0.002]. Follow-up via echo (1.0±0.6 years) demonstrated MR to decrease (≥1 grade) in 31% of patients and increase in 12% of patients. Patients with increased MR after PCI had more severe inferior perfusion defects on baseline MPI (P=0.028), whereas defects in other distributions and LV volumes were similar (P=NS). CONCLUSION The extent and distribution of single-photon emission computed tomography-evidenced myocardial perfusion defects impact MR response to revascularization. An increased magnitude of inferior fixed perfusion defects predicts post-PCI progression of MR.

Response to Letter Regarding Article, “Familial Clustering of Mitral Valve Prolapse in the Community”

Abstract: We thank Dr Barison and colleagues for their interest in our article.1 In our manuscript, we demonstrate that both parental mitral valve prolapse (MVP) and parental mild, nondiagnostic MVP are associated with increased prevalence of MVP in the offspring in the Framingham Heart Study community. In their letter, Barison et al underline the importance of age when assessing MVP prevalence, stating that MVP is more common among older participants in the offspring or generation 2 (Gen 2) than in the younger generation 3 (Gen 3). Based on published Framingham Heart Study literature,2 the prevalence of MVP in Gen 2 is 2.4% at their fifth examination cycle. This percentage is slightly higher in the same cohort at their sixth examination cycle (98/3380 or 2.9%) and at their eighth examination cycle (94/2725 or 3.4%; ie, 11 to 17 years …

Reply to "Letter to the editor: Characterizing preclinical model of ischemic heart failure: difference between LAD and LCx infarctions"

Abstract: reply: We thank Dr Katz and colleagues ([7][1]) for their interest and comments on our recent study ([3][2]) The study was conducted to develop and characterize a large animal model of chronic heart failure (HF) associated with large myocardial infarction (MI) In the six-lead electrocardiography