Abnormal Mechanics Relate to Myocardial Fibrosis and Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

BACKGROUND: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. METHODS: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). RESULTS: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis (P<0.001). An abnormal strain pattern with distinct peaks pre-end-systole and post-end-systole in inferior-lateral wall was frequent in patients with fibrosis (81 versus 26%, P<0.001) but absent in patients without MVP with basal inferior-lateral wall fibrosis (n=20). During median follow-up of 1008 days, 36 of 87 patients with MVP with >6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. CONCLUSIONS: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.

Are Patient Demographics and Payor Status Associated With Practice Patterns in the Surgical Management of Carpal Tunnel Syndrome?

BACKGROUND: Open carpal tunnel release (OCTR) and endoscopic carpal tunnel release (ECTR) are the 2 operative approaches used to treat carpal tunnel syndrome (CTS). This study aims to identify whether differences between OCTR and ECTR rates exist, and, if so, are these differences associated with patient demographics or hospital characteristics. METHODS: The 2018 Nationwide Ambulatory Surgery Sample (NASS) was filtered for patient encounters including either OCTR or ECTR operations. All patients undergoing either OCTR or ECTR were included, regardless of surgical specialty. Patient demographics and hospital characteristics data, provided and predefined by the NASS database, were collected and compared between the 2 treatment groups. RESULTS: A total of 180 740 patient encounters were collected for both procedure types (OCTR: 62.4% women, mean age, 58 years; ECTR: 62.2% women, mean age, 58 years). Patients from lower income zip codes were more likely to undergo OCTR (P < .001). Patients either self-paying (P < .008) or covered by Medicare (P < .001) or Medicaid insurance (P < .001) were also more likely to undergo OCTR. In contrast, patients who received care at academic centers and centers with >300 beds were more likely to undergo ECTR (P < .001). Patients <65 years old were more likely to undergo ECTR (P < .001), and patients > 75 years old were more likely to undergo OCTR (P < .001). In addition, ECTR was found to be more expensive, with average total charges $1568 greater than charges for OCTR (P < .001). CONCLUSIONS: Significant differences exist in treatment strategies for CTS and are related to patient income, location, and primary payor status. Differences in OCTR and ECTR rates are also present, and are related to the size and academic status of hospitals.

Patterns in Academic Cosmetic Surgery Practice: Population Differences and Procedure Preferences.

PURPOSE: Although growth in cosmetic surgery remains constant in the private setting, academic cosmetic surgery practices are often underdeveloped. Our study aims to determine which patient populations access academic cosmetic surgery services. METHODS: The 2018 Health Care Utilization Project Nationwide Ambulatory Surgery Sample database was used for data analysis. Encounters for the following American Society of Plastic Surgery top 5 procedures for 2020 were selected: blepharoplasty, breast augmentation, liposuction, rhinoplasty, and rhytidectomy. Patient encounter data were collected because it relates to median income, geographic location, and primary payer status. RESULTS: The 2018 Nationwide Ambulatory Surgery Sample data set contained 44,078 encounters at academic surgical centers for the procedures listed previously. Low-income patients account for 13.7% of academic cosmetic surgery encounters compared with 37.9% for high-income patients. Breast augmentation rates are higher among low-income patients (20.5% vs 17.2%, P < 0.001), and high-income patients undergo rhytidectomy more frequently (5.7% vs 3.0%, P < 0.001). In the academic setting, patients from large metropolitan areas encompass the majority of cosmetic encounters (71.0%), and these patients are more likely to proceed with rhinoplasty, rhytidectomy, and liposuction procedures (P < 0.001). Patients from smaller metropolitan areas undergo blepharoplasty more frequently compared with those from larger metropolitan areas (56.4% vs 41.8%, P < 0.001). Self-pay and privately insured patients comprise the majority of academic cosmetic surgery encounters (40.8% and 29.9%, respectively). Eighty-eight percent of Medicare patients within this cohort underwent blepharoplasty, whereas self-pay patients accessed breast augmentation, liposuction, and rhytidectomy more often than other insured patients. CONCLUSIONS: Income status, patient location, and primary payer status play an important role in academic cosmetic surgery access rates and procedure preferences. Academic cosmetic practices can use these insights to tailor their services to the populations they serve.

Sauvé-Kapandji and Darrach Salvage Procedure Rates and Perioperative Parameters for Distal Radioulnar Joint Arthritis and Instability.

BACKGROUND: Distal radioulnar joint (DRUJ) instability and arthritis are often painful and functionally limiting pathologies. Two common salvage procedures for DRUJ dysfunction are the Darrach and Sauvé-Kapandji (S-K) procedures. This study aims to provide an analysis of national Darrach and S-K procedure utilization rates and patient demographics. METHODS: A national ambulatory surgery database, the 2018 Nationwide Ambulatory Surgery Sample, was filtered for Darrach and S-K procedure encounters. Data related to patient demographics and medical history, indications for DRUJ salvage, and concurrent hand/wrist procedures were collected. RESULTS: Database analysis revealed 1044 Darrach and 223 S-K procedure encounters. Patients undergoing Darrach procedures were older (60 vs 57, P = .002) and more likely to be women (66.1% vs 54.6%, P < .05). Patients aged <35 years underwent S-K procedures at greater rates compared with Darrach (13.9% vs 8.6%, P < .05). Primary osteoarthritis proved to be the most common indication for DRUJ salvage (64.8%) compared with rheumatoid arthritis (23.2%) and post-traumatic osteoarthritis (12.0%). Darrach and S-K procedures were accompanied by a secondary procedure at rates of 64% and 41%, respectively. The most common secondary procedures were tendon transfer, implant removal, neuroplasty, nerve resections, and wrist arthroscopy. CONCLUSIONS: Patient age and sex are associated with DRUJ salvage procedure selection. Sauvé-Kapandji procedures are used in higher rates in male and younger patient populations. Furthermore, primary osteoarthritis and rheumatoid arthritis are the main underlying pathologies for Darrach and S-K procedures.

DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse.

Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.

Color Doppler Ultrasound versus Computed Tomography Angiography for Preoperative Anterolateral Thigh Flap Perforator Imaging: A Systematic Review and Meta-Analysis.

BACKGROUND: The anterolateral thigh (ALT) perforator flap is a commonly used flap with a predictable, though often variable, perforator anatomy. Preoperative imaging with color Doppler ultrasound (CDU) and computed tomography angiography (CTA) of ALT flap perforators can be a useful tool for flap planning. This study provides a complete review and analysis of the relevant preoperative ALT imaging literature. METHODS: Studies related to preoperative CDU and CTA imaging were reviewed, and information related to imaging method, sensitivity, false-positive rates, and perforator course identification (musculocutaneous vs. septocutaneous) were analyzed. RESULTS: A total of 23 studies related to preoperative ALT flap CDU and CTA imaging were included for review and analysis. Intraoperative perforator identification was compared with those found preoperatively using CDU (n = 672) and CTA (n = 531). Perforator identification sensitivity for CDU was 95.3% (95% CI: 90.9-97.6%) compared with the CTA sensitivity of 90.4% (95% confidence interval [CI]: 74.4-96.9%). The false-positive rate for CDU was 2.8% (95% CI: 1.1-4.5%) compared with 2.4% (95% CI: 0.7-4.1%) for CTA. Accuracy of perforator course identification was 95.5% (95% CI: 93.6-99.2%) for CDU and 96.9% (95% CI: 92.7-100.1%) for CTA. CONCLUSION: CDU provides the reconstructive surgeon with greater preoperative perforator imaging sensitivity compared with CTA; however, false-positive rates are marginally higher with preoperative CDU. Preoperative imaging for ALT flap design is an effective tool, and the reconstructive surgeon should consider the data presented here when selecting a flap imaging modality.

Mitral Valve Prolapse Induces Regionalized Myocardial Fibrosis.

Background Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1S14R/+). Tension-dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension-dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve-induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.

PDGFRα: Expression and Function during Mitral Valve Morphogenesis.

Mitral valve prolapse (MVP) is a common form of valve disease and can lead to serious secondary complications. The recent identification of MVP causal mutations in primary cilia-related genes has prompted the investigation of cilia-mediated mechanisms of disease inception. Here, we investigate the role of platelet-derived growth factor receptor-alpha (PDGFRα), a receptor known to be present on the primary cilium, during valve development using genetically modified mice, biochemical assays, and high-resolution microscopy. While PDGFRα is expressed throughout the ciliated valve interstitium early in development, its expression becomes restricted on the valve endocardium by birth and through adulthood. Conditional ablation of Pdgfra with Nfatc1-enhancer Cre led to significantly enlarged and hypercellular anterior leaflets with disrupted endothelial adhesions, activated ERK1/2, and a dysregulated extracellular matrix. In vitro culture experiments confirmed a role in suppressing ERK1/2 activation while promoting AKT phosphorylation. These data suggest that PDGFRα functions to suppress mesenchymal transformation and disease phenotypes by stabilizing the valve endocardium through an AKT/ERK pathway.

DZIP1 regulates mammalian cardiac valve development through a Cby1-ß-catenin mechanism.

BACKGROUND: Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood. RESULTS: A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and ß-catenin. Co-expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of ß-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of ß-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased ß-catenin activities. The ß-catenin target gene, MMP2 was up-regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype. CONCLUSION: Dzip1 functions to restrain ß-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear ß-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.

Dynamic Expression Profiles of ß-Catenin during Murine Cardiac Valve Development.

ß-catenin has been widely studied in many animal and organ systems across evolution, and gain or loss of function has been linked to a number of human diseases. Yet fundamental knowledge regarding its protein expression and localization remains poorly described. Thus, we sought to define whether there was a temporal and cell-specific regulation of ß-catenin activities that correlate with distinct cardiac morphological events. Our findings indicate that activated nuclear ß-catenin is primarily evident early in gestation. As development proceeds, nuclear ß-catenin is down-regulated and becomes restricted to the membrane in a subset of cardiac progenitor cells. After birth, little ß-catenin is detected in the heart. The co-expression of ß-catenin with its main transcriptional co-factor, Lef1, revealed that Lef1 and ß-catenin expression domains do not extensively overlap in the cardiac valves. These data indicate mutually exclusive roles for Lef1 and ß-catenin in most cardiac cell types during development. Additionally, these data indicate diverse functions for ß-catenin within the nucleus and membrane depending on cell type and gestational timing. Cardiovascular studies should take into careful consideration both nuclear and membrane ß-catenin functions and their potential contributions to cardiac development and disease.

Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.

Non-syndromic mitral valve prolapse (MVP) is the most common heart valve disease affecting 2.4% of the population. Recent studies have identified genetic defects in primary cilia as causative to MVP, although the mechanism of their action is currently unknown. Using a series of gene inactivation approaches, we define a paracrine mechanism by which endocardially-expressed Desert Hedgehog (DHH) activates primary cilia signaling on neighboring valve interstitial cells. High-resolution imaging and functional assays show that DHH de-represses smoothened at the primary cilia, resulting in kinase activation of RAC1 through the RAC1-GEF, TIAM1. Activation of this non-canonical hedgehog pathway stimulates α-smooth actin organization and ECM remodeling. Genetic or pharmacological perturbation of this pathway results in enlarged valves that progress to a myxomatous phenotype, similar to valves seen in MVP patients. These data identify a potential molecular origin for MVP as well as establish a paracrine DHH-primary cilium cross-talk mechanism that is likely applicable across developmental tissue types.

Tugging at the Heart Strings: The Septin Cytoskeleton in Heart Development and Disease.

Septin genes were originally identified in budding yeast in 1971. Since their original discovery, at least 13 mammalian genes have now been found, which give rise to a vast array of alternatively spliced proteins that display unique spatial-temporal function across organs systems. Septin's are now recognized as the 4th major component of the cytoskeleton. Their role in regulating ciliogenesis, actin and microtubule organization and their involvement in mechanotransduction clearly solidify their place as both a responder and driver of cellular activity. Although work on septin's has escalated over the past decades, knowledge of septin function in the heart remains rudimentary. Whereas many cardiovascular diseases have been associated with genetic loci that include septin genes, new and additional concerted efforts will likely uncover previously unrecognized mechanisms by which the septin class of proteins contribute to clinical cardiac phenotypes. In this review, we place known function of septin proteins in the context of heart development and disease and provide perspectives on how increased knowledge of these proteins can mechanistically inform cardiac pathologies.

Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis.

BACKGROUND: Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities. METHODS: We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography. RESULTS: Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models. CONCLUSIONS: These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.

Primary cilia defects causing mitral valve prolapse.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1 A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

Effects of Astaxanthin on the Proliferation and Migration of Breast Cancer Cells In Vitro.

Astaxanthin (ASX) is a marine-based ketocarotenoid; an accessory pigment in plants in that it has many different potential functions. ASX is an antioxidant that is notably more potent than many other antioxidants. Antioxidants have anti-inflammatory and oxidative stress-reducing properties to potentially reduce the incidence of cancer or inhibit the expansion of tumor cells. In this study, we tested the hypothesis that ASX would inhibit proliferation and migration of breast cancer cells in vitro. We found that application of ASX significantly reduced proliferation rates and inhibited breast cancer cell migration compared to control normal breast epithelial cells. Based on these results, further investigation of the effects of ASX on not only breast cancer cells, but other forms of tumor cells, should be carried out.