Mutations in DCHS1 Cause Mitral Valve Prolapse

SUMMARY Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1–3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic etiology 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 homolog dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 mRNA 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 etiological 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

Lead Burden as a Factor for Higher Complication Rate in Patients With Implantable Cardiac Devices

Purpose Lead revisions have increased over the last decade. Patients who do not undergo lead extraction face an increased lead burden. Consequences of increased lead burden have not been fully defined. We sought to characterize the complication rate and outcomes in patients with sterile redundant leads. Methods We retrospectively reviewed 242 consecutive patients [mean age 74 ± 12 years; 66.9% male] who underwent lead revision that resulted in an abandoned lead from January 2005 to June 2010. Patients were placed in a cohort based on number of leads after last recorded procedure (Group A: ≤2 [n=58]; Group B: 3-4 [n=168]; Group C: ≥5 [n=16]). Prespecified inhospital and long-term follow-up events were compared. Mortality rates were obtained from Social Security Death Index. Median follow-up was 2 years. Results Baseline age, gender and race demographics were similar among the three groups. Increasing lead burden was associated with more adverse periprocedural events (A: 3.4%, B: 10.1%, C: 25.0%; P=0.031) and long-term device-related events (A: 1.7%, B: 13.0%, C: 18.8%; P=0.031). Device-related readmissions increased in frequency as lead burden increased (A: 3.5%, B: 18.5%, C: 37.5%; P=0.002). Combined periprocedural and late events also increased with more redundant leads (A: 5.2%, B: 23.2%, C: 44.0%; P=0.001). Total major events were infrequent (3.3%). There was no procedure-related mortality. Long-term all-cause mortality was not significantly different (A: 17.2%, B: 23.8%, C: 25.0%; P=0.567). Conclusions Greater lead burden was associated with increased number of periprocedural and long-term minor events. It did not significantly impact major events or mortality

Left atrial laceration with epicardial ligation device

Many new devices and techniques are being developed to attempt a reduction in embolic stroke risk for patients with atrial fibrillation who are either unable or unwilling to maintain long-term anticoagulation. One of these new devices (LARIAT(®), SentreHEART Inc., Redwood City, California, USA) employs delivery of an epicardial suture to ligate the left atrial appendage after percutaneous pericardial and transseptal access. This series presents three clinical cases that demonstrate a serious and recurrent complication of left atrial laceration and cardiac tamponade shortly following delivery of an epicardial suture ligation to the left atrial appendage. Three clinical cases are described in detail with pre- and postprocedure angiography and echocardiography as well as illustrations reflecting the surgeon\u27s findings on direct visualization of the left atrial lacerations postligation. Potential hypotheses of each injury are examined in light of the case timelines and findings at sternotomy. There was no suggestion that tamponade was related to pericardial or transseptal access, but rather a complication with device delivery. These three patients quickly progressed to clinical cardiac tamponade despite attempted drainage, stressing the importance of cardiovascular surgery backup, including a cardiopulmonary bypass pump, when delivering novel, percutaneous ligation devices for the left atrial appendage