Evaluating Mitral TEER in the Management of Moderate Secondary Mitral Regurgitation Among Heart Failure Patients.

BACKGROUND: Moderate secondary mitral regurgitation (SMR) represents a subgroup of heart failure (HF) patients with treatment restricted to medical therapy. Outcomes in patients with moderate SMR treated with mitral transcatheter edge-to-edge repair (M-TEER) are less well known. OBJECTIVES: The aim of this study was to assess the safety and effectiveness of M-TEER in subjects with moderate SMR using the EXPANDed studies. METHODS: One-year outcomes in subjects from the EXPANDed studies (EXPAND [A Contemporary, Prospective Study Evaluating Real-world Experience of Performance and Safety for the Next Generation of MitraClip Devices] and EXPAND G4 [A Post-Market Study Assessment of the Safety and Performance of the MitraClip G4 System] MitraClip studies) with baseline moderate SMR (2+), per echocardiographic core laboratory (ECL) assessment, were compared with subjects with baseline severe SMR (≥3+). RESULTS: There were 335 subjects with moderate SMR and 525 with severe SMR at baseline per ECL review. Baseline characteristics were similar between the 2 subgroups. After treatment with M-TEER, significant MR reduction was achieved in both groups. Significant left ventricular (LV) reverse remodeling was observed through 1 year, with a >20 mL decrease in LV end-diastolic and end-systolic volumes on average in the moderate SMR group. Significant 1-year improvements in NYHA functional class (>78% NYHA functional class I or II) and quality of life (>20 points on the Kansas City Cardiomyopathy Questionnaire-Overall Summary) were observed in subjects with moderate SMR. Similarly, low rates of major adverse events, all-cause mortality, and HF hospitalizations were observed between the 2 subgroups through 1 year. CONCLUSIONS: In the EXPANDed studies, subjects with moderate SMR treated with M-TEER had improvements similar to subjects with severe SMR in quality of life and positive LV remodeling at 1 year. Future studies are needed to evaluate if M-TEER would be beneficial for HF patients with moderate SMR.

Appropriate Statistical Methods to Assess Cross-study Diagnostic 23-Gene Expression Profile Test Performance for Cutaneous Melanocytic Neoplasms.

ABSTRACT: Comparing studies of molecular ancillary diagnostic tests for difficult-to-diagnose cutaneous melanocytic neoplasms presents a methodological challenge, given the disparate ways accuracy metrics are calculated. A recent report by Boothby-Shoemaker et al investigating the real-world accuracy of the 23-gene expression profile (23-GEP) test highlights this methodological difficulty, reporting lower accuracy than previously observed. However, their calculation method-with indeterminate test results defined as either false positive or false negative-was different than those used in previous studies. We corrected for these differences and recalculated their reported accuracy metrics in the same manner as the previous studies to enable appropriate comparison with previously published reports. This corrected analysis showed a sensitivity of 92.1% (95% confidence interval [CI], 82.1%-100%) and specificity of 94.4% (91.6%-96.9%). We then compared these results directly to previous studies with >25 benign and >25 malignant cases with outcomes and/or concordant histopathological diagnosis by ≥3 dermatopathologists. All studies assessed had enrollment imbalances of benign versus malignant patients (0.8-7.0 ratio), so balanced cohorts were resampled according to the lowest common denominator to calculate point estimates and CIs for accuracy metrics. Overall, we found no statistically significant differences in the ranges of 23-GEP sensitivity, 90.4%-96.3% (95% CI, 80.8%-100%), specificity, 87.3%-96.2% (78.2%-100%), positive predictive value, 88.5%-96.1% (81.5%-100%), or negative predictive value, 91.1%-96.3% (83.6%-100%) between previous studies and the cohort from Boothby-Shoemaker et al with this unified methodological approach. Rigorous standardization of calculation methods is necessary when the goal is direct cross-study comparability.

Dose-dependent effects of Dnmt3a in an inducible murine model of KrasG12D-driven leukemia.

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies, including acute myeloid leukemia. An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly comutated genes in myeloid malignancies, such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ERT2 murine model systems to study the effects of constitutively active KrasG12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of diverse nonhematologic tumors appearing after tamoxifen induction, we employed a transplantation model. With pretransplant tamoxifen induction, most Kras mice died quickly of T-cell malignancies regardless of Dnmt3a status. Using posttransplant induction, we observed a dose-dependent effect of DNMT3A depletion that skewed the leukemic phenotype toward a myeloid lineage. Specifically, 64% of 3aKO/Kras mice had exclusively myeloid disease compared with 36% of 3aHet/Kras and only 13% of Kras mice. Here, 3aKO combined with Kras led to increased disease burden, multiorgan infiltration, and faster disease progression. DOT1L inhibition exerted profound antileukemic effects in malignant 3aKO/Kras cells, but not malignant cells with Kras mutation alone, consistent with the known sensitivity of DNMT3A-mutant leukemia to DOT1L inhibition. RNAseq from malignant myeloid cells revealed that biallelic Dnmt3a deletion was associated with loss of cell-cycle regulation, MYC activation, and TNF⍺ signaling. Overall, we developed a robust model system for mechanistic and preclinical investigations of acute myeloid leukemia with DNMT3A and Ras-pathway lesions.

A clinical impact study of dermatologists' use of diagnostic gene expression profile testing to guide patient management.

Aim: Cutaneous melanocytic neoplasms with diagnostic and/or clinical ambiguity pose patient management challenges. Methods: Six randomized case scenarios with diagnostic/clinical uncertainty were described with/without a benign or malignant diagnostic gene expression profile (GEP) result. Results: Clinical impact was assessed by reporting the mean increase/decrease of management changes normalized to baseline (n = 32 dermatologists). Benign GEP results prompted clinicians to decrease surgical margins (84.2%). Malignant GEP results escalated surgical excision recommendations (100%). A majority (72.2%) reduced and nearly all (98.9%) increased follow-up frequency for benign or malignant GEP results, respectively. There was an overall increase in management plan confidence with GEP results. Conclusion: Diagnostic GEP tests help guide clinical decision-making in a variety of diagnostically ambiguous or clinicopathologically discordant scenarios.

Dermatologists' use of diagnostic gene expression profiles for personalized patient care. When your doctor takes a piece of a mole, that mole is looked at under the microscope by a pathologist. The pathologist is responsible for figuring out if the mole is dangerous or not. Dangerous moles are removed with surgery to make sure all the dangerous tissue is gone. Moles without a health threat are left alone. Sometimes figuring out how dangerous a mole is is difficult. The pathologist may not provide the doctor with enough information for them to know how to treat your mole. There is a test that can provide information on whether your mole is unsafe. This test is called diagnostic gene expression profiling or GEP. In this study, GEP is used to help doctors figure out how to treat a mole and how often the patient should be seen in the office for skin checks. With GEP, important changes in patient treatment were identified. These include the need for an additional surgery, how much healthy tissue should be removed during surgery and how often the patient should be seen in the office. For suspicious moles where the pathology report is unclear, GEP can provide information that leads to more appropriate and personalized patient care.

Ancillary diagnostic gene expression profile testing for ambiguous cutaneous melanocytic lesions helps optimize dermatologist recommendations for excision margin and follow-up.

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities.

IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-cell acute lymphoblastic leukemia. Due to the heterogeneity of concomitant lesions, it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance, and whether their consideration as a prognostic indicator is valuable in improving outcome. CRISPR/Cas9 strategies were used to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment that can be linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of common therapies for B-cell acute lymphoblastic leukemia, including dexamethasone, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. A CRISPR homology-directed repair strategy was also used to knock-in the dominant-negative IK6 isoform into the endogenous locus, and a similar drug resistance profile, with the exception of retained dexamethasone sensitivity, was observed. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, likely owing to marked downregulation of SAMHD1 after IKZF1 knockout. Both types of IKZF1 lesions decreased the survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.

Transseptal chordal replacement: early experience.

Chordal replacement is a fundamental technique used in the surgical repair of primary mitral regurgitation, and can be an effective means of preserving the native valve without leaflet resection. Surgical chordal replacement can be challenging since it is performed on an open, non-beating heart, and choosing the correct chord length to restore the zone of coaptation requires both intuition and skill. Developing transcatheter, transfemoral, and transseptal approaches to mitral valve chordal replacement presents the opportunity for safer and potentially earlier treatment of patients with primary mitral regurgitation. In particular, transcatheter methods will allow adjustment of chordal length and position real-time on a beating heart under echocardiographic guidance. In this manuscript, we review the current transcatheter transseptal technologies in development and discuss the various issues related to device design, efficacy, durability, and clinical trial design.

Transseptal direct complete annuloplasty: early experience.

Annuloplasty is a fundamental component of surgical mitral valve repair, and is employed in nearly 100% of repair operations for both primary and secondary mitral regurgitation (SMR). Developing transcatheter techniques to replicate surgical annuloplasty has been the focus of significant innovation and development in recent years. Since many patients are not offered surgery due to high perceived surgical risk, transcatheter approaches will provide new treatment options. In this manuscript, we review technologies which allow transseptal and transcatheter mitral valve (MV) annuloplasty.

Intracardiac echocardiographic-guided right-sided cardiac biopsy: Case series and literature review.

Endomyocardial biopsy (EMB) is a common procedure used to aid in the diagnosis of diffuse myocardial diseases and, less commonly, in the diagnosis of cardiac tumors. As cardiac tumors are often found in high-risk locations (ventricular free wall or atria), precision biopsy is paramount, and additional imaging, like transesophageal echocardiography is often required for guidance. The use of intracardiac echocardiography (ICE) to guide biopsy has been described, but there is no consensus on a standardized approach. We report our institutional approach with three cases of ICE-directed EMB performed with the 2.4 mm Jawz bioptome directed with an 8.5-Fr Agilis NxT steerable introducer. All cases were performed under guidance with the AcuNav ICE probe. There were no procedural complications and a definitive diagnosis was obtained in all three cases. We also review the available published cases of ICE-guided EMB in the literature-noting the different procedural approaches, complication rate, and diagnostic yield. There were only two negative biopsies reported among the published cases and no reported complications. Our review of all these cases suggests that ICE-guidance for EMB is superior to other forms of imaging in its ease of use and high definition of right-sided cardiac structures. We also feel that the use of the Agilis steerable sheath allows for more precise directing of the bioptome and is a critical component in performing a successful targeted biopsy.

Transjugular mitral valve repair with the MitraClip: A step-by-step guide.

The MitraClip procedure is carried out almost exclusively via the transfemoral approach. However, in some patients transfemoral delivery of MitraClip is not technically feasible (e.g., occluded inferior vena cava or tortuous/obstructive iliofemoral venous anatomy). The technical considerations and challenges of the MitraClip procedure are amplified when an alternate route is considered. We describe a successful case of MitraClip performed via the right internal jugular (IJ) approach in a patient with a flail A3 scallop and previous mitral valve repair. We reviewed prior cases in the literature and discuss step-by-step the pertinent clinical and technical considerations for performing this procedure via the transjugular route. In summary, the right IJ access site provides a reasonable alternative to perform the MitraClip procedure in cases where femoral access is contraindicated or prohibitive. A thorough understanding of the technical considerations is crucial in improving procedural success rates.

Initial clinical experience with the FlexPoint Steerable Transseptal Needle in left-sided structural heart procedures.

OBJECTIVES: The purpose of this study is to describe the initial clinical experience with a steerable transseptal needle (STSN) for left-sided structural heart procedures. BACKGROUND: Targeted transseptal (TS) puncture is required for many structural heart procedures, and the use of a steerable needle has not previously been described. METHODS: Consecutive patients undergoing structural heart interventions with targeted TS puncture under transesophageal echocardiographic (TEE) and fluoroscopic guidance were studied. The STSN was used in all patients with a standard commercial TS sheath. Deflection of the needle was performed "real time" to achieve localization of the TS puncture site. RESULTS: Twenty-seven patients underwent STSN puncture of the interatrial septum. In all cases, the needle could be deflected in vivo to achieve optimal tenting and localization of the puncture site without having to remove or reshape the needle. The needle was deflected to match a wide range of right atrial diameters (width 4.3 ± 0.9 cm and length 6.0 ± 0.9 cm in the 4-chamber view). In two patients with prior mitral valve surgery and a fibrotic septum, assisted crossing was achieved using the piercing stylet in one patient, and Bovie energy in the other. There were no procedural complications, and all patients had successful completion of the intended structural heart procedure. CONCLUSIONS: The STSN needle can be used to target the intended puncture location on the interatrial septum with real-time adjustable deflection without the need to remove and reshape the needle. In all cases crossing was successful and there were no complications.

Early clinical results with the Tendyne transcatheter mitral valve replacement system.

Transcatheter mitral valve replacement is an emerging technology for the treatment of mitral valve regurgitation. Numerous devices are in development and in various stages of clinical investigation. The Tendyne system (Tendyne Holdings, LLC, a subsidiary of Abbott Vascular, Roseville, Minnesota) is a fully repositionable and retrievable, transapical transcatheter mitral valve replacement platform. The results of the early feasibility studies in the U.S. are highly encouraging and a pivotal randomized trial is underway. The Tendyne transcatheter mitral valve replacement valve may prove to be a safe, less invasive approach to treatment of mitral valve disease.

Early experience with Millipede IRIS transcatheter mitral annuloplasty.

The IRIS mitral annuloplasty ring is a transcatheter, transfemoral and transseptal-delivered complete, semi-rigid annuloplasty ring. The IRIS system mimics surgical annuloplasty by reducing the mitral septal-lateral dimension and improving leaflet coaptation. We report the early experience with the IRIS system in seven patients. These patients had 3-4+ mitral regurgitation (MR) with annular dilation and were symptomatic NYHA II-IV with LV end systolic dimensions ≤65 mm. Patients were excluded for LVEF <20%, aortic valve disease, right-sided heart failure and PA systolic pressure >70 mmHg. Baseline and 30-day transthoracic echocardiography and CT imaging was performed. In phase 1, 4 patients had surgical IRIS mitral ring implantation. In phase 2, 3 patients had transfemoral, transseptal delivery of the IRIS mitral ring. There was no procedural death, or MI. The mitral SL diameter was reduced from 38.0±4.1 to 25.9±4.9 mm at 30 days (31.8% SL reduction, n=7). MR was reduced from baseline 3-4+ to 0-1+ in all patients at 30 days. There were improvements in NYHA class and there was a decrease in diastolic LV volumes from 182.4±54.3 to 115.3±98.8 mL at 30 days (36.8% reduction). Based on these initial positive findings, ongoing clinical trials are underway to further evaluate the safety and efficacy of the IRIS ring.

Oral Mucosa Harbors a High Frequency of Endothelial Cells: A Novel Postnatal Cell Source for Angiogenic Regeneration.

Endothelial progenitor cells/endothelial cells (EPCs/ECs) have great potential to treat pathological conditions such as cardiac infarction, muscle ischemia, and bone fractures, but isolation of EPC/ECs from existing cell sources is challenging due to their low EC frequency. We have isolated endothelial progenitor (EP)-like cells from rat oral mucosa and characterized their yield, immunophenotype, growth, and in vivo angiogenic potential. The frequency of EP-like cells derived from oral mucosa is thousands of folds higher than EPCs derived from donor-match bone marrow samples. EP-like cells from oral mucosa were positive for EC markers CD31, VE-Cadherin, and VEGFR2. Oral mucosa-derived EP-like cells displayed robust uptake of acetylated low-density lipoprotein and formed stable capillary networks in Matrigel. Subcutaneously implanted oral mucosa-derived EP-like cells anastomosed with host blood vessels, implicating their ability to elicit angiogenesis. Similar to endothelial colony-forming cells, EP-like cells from oral mucosa have a significantly higher proliferative rate than human umbilical vein endothelial cells. These findings identify a putative EPC source that is easily accessible in the oral cavity, potentially from discarded tissue specimens, and yet with robust yield and potency for angiogenesis in tissue and organ regeneration.

DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia.

Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia and portend a poor prognosis; thus, new therapeutic strategies are needed. The likely mechanism by which DNMT3A loss contributes to leukemogenesis is altered DNA methylation and the attendant gene expression changes; however, our current understanding is incomplete. We observed that murine hematopoietic stem cells (HSCs) in which Dnmt3a had been conditionally deleted markedly overexpress the histone 3 lysine 79 (H3K79) methyltransferase, Dot1l. We demonstrate that Dnmt3a(-/-) HSCs have increased H3K79 methylation relative to wild-type (WT) HSCs, with the greatest increases noted at DNA methylation canyons, which are regions highly enriched for genes dysregulated in leukemia and prone to DNA methylation loss with Dnmt3a deletion. These findings led us to explore DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML. We show that pharmacologic inhibition of DOT1L resulted in decreased expression of oncogenic canyon-associated genes and led to dose- and time-dependent inhibition of proliferation, induction of apoptosis, cell-cycle arrest, and terminal differentiation in DNMT3A-mutant cell lines in vitro. We show in vivo efficacy of the DOT1L inhibitor EPZ5676 in a nude rat xenograft model of DNMT3A-mutant AML. DOT1L inhibition was also effective against primary patient DNMT3A-mutant AML samples, reducing colony-forming capacity (CFC) and inducing terminal differentiation in vitro. These studies suggest that DOT1L may play a critical role in DNMT3A-mutant leukemia. With pharmacologic inhibitors of DOT1L already in clinical trials, DOT1L could be an immediately actionable therapeutic target for the treatment of this poor prognosis disease.

E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding.

Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of the MCSFR promoter through antagonizing PU.1's ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages.

Approaches to the management of functional tricuspid regurgitation.

Functional tricuspid regurgitation (FTR) is an acquired valvular abnormality that is most frequently encountered during the evaluation and operative management of left-sided heart failure and left heart valve disease. Observational studies have demonstrated that uncorrected significant FTR during mitral valve surgery can result in inferior early and late outcomes due to progression of FTR and underlying right heart failure. The 2012 ESC/EACTS and 2014 ACC/AHA guidelines strongly encourage the surgical correction of greater than mild tricuspid regurgitation or tricuspid annular dilation greater than 4 cm in patients undergoing left-sided valve surgery. Prospective randomized trials are needed to bolster the evidence behind the current recommendations. Percutaneous therapies in development may eventually result in less invasive options for treating FTR.

Long-term outcomes of angiographically confirmed coronary stent thrombosis: results from a multicentre California registry.

AIMS: Limited data exist on long-term outcomes of patients with stent thrombosis (ST). Our aim was to describe the long-term outcomes after angiographically confirmed ST. METHODS AND RESULTS: In this multicentre registry, consecutive cases of definite ST were identified between 2005 and 2013. Clinical and procedural characteristics, in-hospital outcomes and long-term survival up to five years were compared between those with and those without adverse cardiovascular and cerebrovascular events (MACCE), defined as all-cause mortality, myocardial infarction and stroke. Two hundred and twenty-one patients with 239 stent thrombosis events were identified. Patients who developed MACCE were older, less likely to be men, and less likely to have hypertension. Angiographic characteristics were similar. Patients who had a MACCE event showed a trend towards a lower likelihood of procedural success (86% vs. 91%, p=0.05). MACCE rates were 22% at one year and 41% at five years. All-cause mortality was 13% at one year and 24% at five years. On multivariable analysis, age, diabetes mellitus, active smoking and ST at a bifurcation were independently associated with the occurrence of MACCE up to five years. CONCLUSIONS: Age, active smoking, diabetes mellitus and bifurcation disease are independently associated with long-term MACCE over a five-year follow-up period.

Transcatheter repair of aortic leaflet perforation in a patient with prior surgical bicuspid aortic valve repair.

A 47-year-old male underwent surgery for functional bicuspid aortic valve severe regurgitation with a fused right and left coronary cusp. The patient presents nine years after surgical bicuspid aortic valve repair with symptomatic severe aortic regurgitation, diagnosed by TEE and MRI, caused primarily from a perforation located at the base of the surgically fused coronary cusps. The patient had a minimally dilated aortic root that did not yet necessitate surgical intervention. We present a novel percutaneous bicuspid aortic valve perforation repair that potentially decreases the number of surgical operations the patient must undergo during his lifetime.

Balloon dilation atrial septostomy for advanced pulmonary hypertension in patients on prostanoid therapy.

BACKGROUND: Prostanoid therapy improves quality of life and may increase survival in patients with advanced pulmonary hypertension (PH). Balloon dilated atrial septostomy (BDAS) can palliate or bridge to transplantation for patients resistant to medical therapy. The safety and efficacy of BDAS in the prostanoid era has not previously been reported. METHODS: All patients had progressive symptoms despite prostanoid therapy at the time of their first BDAS. Sixteen patients who underwent a total of 23 septostomies between 2004 and 2014 were included in this retrospective case series. RESULTS: Patients were aged 47.6 years ± 11.3 with 12/16 women. Etiologies included idiopathic (7), methamphetamine (6), scleroderma (1), and anorexigen (2). One patient died within 24 hr post-procedure. Thirty-day and 1-year survival were 75% and 64%, respectively. Six of the septostomies were revisions, including two which were ultimately stented. Three subjects were successfully bridged to transplant. Pulmonary capillary wedge pressure (PCWP) increased from a mean of 13 to 17 mm Hg, cardiac index increased from 2.1 to 2.4 L/min/m(2) , and arterial saturation decreased from 90.7 ± 4.3 to 82.5 ± 5.6%. All non-survivors at 30 days were male and had higher baseline serum creatinine, mean RAP, right ventricular end diastolic pressure (RVEDP), and left ventricle (LV) filling pressures, and lower right ventricle (RV) ejection fraction. Mortality was associated with unchanged post-septostomy cardiac output despite an increase in left ventricular end diastolic pressure (LVEDP). CONCLUSIONS: BDAS may be an alternate therapy for select PH patients who have symptomatic progression despite prostanoid therapy. Survival is comparable to prior reports of BDAS in the pre-prostanoid era.