Survival and readmission among patients with advanced cardiomyopathy undergoing transcatheter edge-to-edge mitral valve repair: Are we applying COAPT findings too broadly?

OBJECTIVE: Transcathether edge-to-edge mitral valve repair (TEER) has been shown to be an effective treatment for secondary mitral regurgitation (MR). However, the outcomes of TEER in patients with severe cardiomyopathy is less clear. The objective of this study is to determine the outcomes of such patients who underwent TEER at our institution. METHODS: A retrospective review of patients with severe cardiomyopathy, defined as ejection fraction ≤30% or the requirement of inotropic support preoperatively, undergoing TEER for secondary MR at our institution from 11/2016 to 11/2020 was performed. Univariate analysis associating preoperative characteristics with our primary endpoint of 1-year death or orthotopic heart transplant (OHT) was performed. Kaplan-Meier analysis was conducted for the composite outcome of death or OHT, as well as for heart failure-related readmission. Finally, an assessment of changes in MR severity from the preoperative, to immediate postoperative period, to 30-day postoperative period was conducted. RESULTS: There were 48 patients identified. Median age was 74.5 years (IQR 65.5-79.5), median ejection fraction was 21.5% (IQR 16.0-27.5), and 81.4% of patients had severe or torrential mitral regurgitation preoperatively. The composite endpoint of 1-year mortality or OHT occurred in 15 of 48 patients (31.3%, 14 deaths and 1 OHT). One-year heart failure readmission rate was 47.9%. Mortality or OHT at 2 years occurred in 45.8%. CONCLUSION: Patients at extremes of heart failure who underwent TEER had poor outcomes when assessed at 1-year. Our study may suggest that the results of cardiovascular outcomes assessment of the mitraclip percutaneous therapy for heart failure patients with secondary mitral regurgitation may not be applicable to patients with severe cardiomyopathy.

Racial and socioeconomic disparities in urgent transcatheter mitral valve repair: A National Inpatient Sample analysis.

BACKGROUND: Cardiac interventions performed urgently are known to be associated with poor outcomes compared with electively performed procedures. Transcatheter edge-to-edge mitral valve repair (TMVr) has developed as a reasonable alternative to mitral valve surgery in certain patient populations. We aimed to leverage a national database to identify predictors of urgent versus elective TMVr, as well as the association between urgency and outcomes. METHODS: The National Inpatient Sample (NIS) was queried to identify patients who underwent TMVr from 2016 to 2017. Hospitalizations were identified within the database as elective versus nonelective. Univariate and multivariable analyses were performed to identify patient characteristics associated with urgent procedures. In-hospital outcomes were assessed. RESULTS: There were 10,195 cases of TMVr in this cohort, 24.2% of which were performed urgently. In multivariable analysis, Hispanic race, Medicaid insurance, and low income were associated with increased likelihood of urgent hospital admission and TMVr. Additionally, small hospital size and Northeast region were associated with increased likelihood of urgent admission and procedure. Urgent TMVr was associated with increased mortality (4.5% vs. 1.6%, p < .001), prolonged length of stay (6.0 vs. 2.0, p < .001), and increased cost ($71,451.90 vs. $44,981.20, p < .001). CONCLUSIONS: Racial and socioeconomic disparities exist in the utilization of TMVr as an urgent versus elective procedure, suggesting differences in access to surveillance and preventive care. Urgent TMVr is associated with increased morbidity and mortality, prolonged length of stay, and increased hospital costs. Priority should be placed on mitigating such disparities to improve outcomes.

Multifocal extracranial mycotic aneurysms in a patient with endocarditis.

This report describes the case of a 44-year-old man with Streptococcus gallolyticus (formerly S. bovis) endocarditis requiring surgical mitral valve replacement who developed multifocal extracranial mycotic aneurysms after the resolution of infection.

Heparin-induced thrombocytopenia in patients readmitted after open cardiac surgical procedures: A case series.

Objectives: Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that occurs in a small percentage of patients exposed to heparin. Concerns of HIT are particularly high in patients undergoing cardiac procedures requiring cardiopulmonary bypass, as they are exposed to high doses of heparin intraoperatively. Our aim was to identify and assess the hospital courses of patients who were diagnosed with HIT during readmission following cardiac surgery. Methods: A retrospective review of patients who underwent open cardiac surgical procedures from June 2017 through October 2019 was performed. Of these, we identified patients who were newly diagnosed with HIT upon readmission. HIT positivity was defined as a positive anti-PF4 antibody screening test, plus a positive serotonin release assay. Results: Of the 2496 patients identified, 13 patients were HIT positive on index admission and were excluded. Of the remaining 2483 patients, 351 were readmitted within 30 days. Six were newly diagnosed with HIT during readmission, 5 of whom presented with thrombotic complications. One patient was readmitted with thrombocytopenia and was started on argatroban; the remaining 5 did not have a significantly lower platelet count on readmission. Of the 12 patients readmitted for venous thromboembolism, 4 tested positive for HIT. Conclusions: HIT can have a delayed appearance following open heart surgery. Venous thromboembolism appears to be a significant indicator for HIT during readmission, even in the absence of thrombocytopenia. This may support the use of non-heparin anticoagulation for cardiac surgery patients readmitted with thromboembolism until HIT status is determined.

Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack.

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8⁺ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.

Nonproteolytic roles of 19S ATPases in transcription of CIITApIV genes.

Accumulating evidence shows the 26S proteasome is involved in the regulation of gene expression. We and others have demonstrated that proteasome components bind to sites of gene transcription, regulate covalent modifications to histones, and are involved in the assembly of activator complexes in mammalian cells. The mechanisms by which the proteasome influences transcription remain unclear, although prior observations suggest both proteolytic and non-proteolytic activities. Here, we define novel, non-proteolytic, roles for each of the three 19S heterodimers, represented by the 19S ATPases Sug1, S7, and S6a, in mammalian gene expression using the inflammatory gene CIITApIV. These 19S ATPases are recruited to induced CIITApIV promoters and also associate with CIITA coding regions. Additionally, these ATPases interact with elongation factor PTEFb complex members CDK9 and Hexim-1 and with Ser5 phosphorylated RNA Pol II. Both the generation of transcripts from CIITApIV and efficient recruitment of RNA Pol II to CIITApIV are negatively impacted by siRNA mediated knockdown of these 19S ATPases. Together, these results define novel roles for 19S ATPases in mammalian gene expression and indicate roles for these ATPases in promoting transcription processes.

E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction.

Mutations in cardiac myosin binding protein C (cMyBP-C) are prevalent causes of hypertrophic cardiomyopathy (HCM). Although HCM-causing truncation mutations in cMyBP-C are well studied, the growing number of disease-related cMyBP-C missense mutations remain poorly understood. Our objective was to define the primary contractile effect and molecular disease mechanisms of the prevalent cMyBP-C E258K HCM-causing mutation in nonremodeled murine engineered cardiac tissue (mECT). Wild-type and human E258K cMyBP-C were expressed in mECT lacking endogenous mouse cMyBP-C through adenoviral-mediated gene transfer. Expression of E258K cMyBP-C did not affect cardiac cell survival and was appropriately incorporated into the cardiac sarcomere. Functionally, expression of E258K cMyBP-C caused accelerated contractile kinetics and severely compromised twitch force amplitude in mECT. Yeast two-hybrid analysis revealed that E258K cMyBP-C abolished interaction between the N terminal of cMyBP-C and myosin heavy chain sub-fragment 2 (S2). Furthermore, this mutation increased the affinity between the N terminal of cMyBP-C and actin. Assessment of phosphorylation of three serine residues in cMyBP-C showed that aberrant phosphorylation of cMyBP-C is unlikely to be responsible for altering these interactions. We show that the E258K mutation in cMyBP-C abolishes interaction between N-terminal cMyBP-C and myosin S2 by directly disrupting the cMyBP-C-S2 interface, independent of cMyBP-C phosphorylation. Similar to cMyBP-C ablation or phosphorylation, abolition of this inhibitory interaction accelerates contractile kinetics. Additionally, the E258K mutation impaired force production of mECT, which suggests that in addition to the loss of physiological function, this mutation disrupts contractility possibly by tethering the thick and thin filament or acting as an internal load.

Supercooled aqueous nuclear magnetic resonance using agarose gels.

Low-temperature nuclear magnetic resonance (NMR), especially under supercooled conditions, can give critical insight into biomolecular systems via slowed dynamics and exchange rates. These conditions can also increase correlation times of small molecules, potentially allowing for NMR structural study of small molecules at moderate field strengths. Agarose gels allow for supercooled conditions and are simple to prepare, invisible to NMR, and noninteractive with most biomolecules and organics. Here we demonstrate their use with nucleic acids, small organic molecules, and peptides.

Recognition of damaged DNA: structure and dynamic markers.

DNA damage, a consequence of external factors and inherent metabolic processes, is omnipresent. Nature has devised multiple strategies to safeguard the genetic information and developed intricate repair mechanisms and pathways to reverse an array of different DNA lesions, including mismatches. Failure of the DNA repair systems may result in mutation, premature ageing, and cancer. In this review, we focus on structural and dynamic aspects of detection of lesions in base excision and mismatch repair. A thorough understanding of repair, pathways, and regulation is necessary to develop strategies for targeting DNA-related pathologies.

DNA sequence context conceals α-anomeric lesions.

DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an α-anomeric adenosine (αA) flanked by cytosines (5'CαAC-3') resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5'CαAG-3' motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5'CαAG-3' core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total R(X) <5.3%). The αA base is intrahelical, in a reverse Watson-Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5'CαAC-3' core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5'CαAC-3' sequence. The improved stacking of the 5'CαAG-3' core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV.