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Annals of Cardiothoracic Surgery Jul 2023Aortic root remodeling was originally designed in the late 1980s to treat patients with tricuspid aortic valves (TAVs), aortic regurgitation (AR), and root aneurysm to...
Aortic root remodeling was originally designed in the late 1980s to treat patients with tricuspid aortic valves (TAVs), aortic regurgitation (AR), and root aneurysm to normalize root dimensions. The late results showed a relevant proportion of patients who required reoperation for recurrent AR. Later observations revealed that cusp prolapse is frequently present after correction of root dilatation. We showed that such prolapse could be detected by measuring effective height (eH) and corrected by concomitant cusp repair. In the past 13 years, we have added a suture annuloplasty to improve aortic valve function further. The operation starts with ascertaining adequate cusp size by measuring geometric cusp height. The dilated aortic wall is resected, and a Dacron graft is tailored to create three tongues. These tongues are sutured to the cusp insertion lines. Starting the suture in the nadir allows for easy extension of tongue length to avoid commissural height restriction. A suture annuloplasty is added at nadir level and tied around a Hegar dilator to normalize annular diameter. The valve is assessed visually and by measuring eH. Cusp prolapse (eH <9 mm) is frequent and corrected by free margin plication until all free margins are at equal level and eH is 9 mm. We have employed root remodeling in more than 710 instances of root aneurysm and TAVs. Mean myocardial ischemic time has been 65±13 minutes for isolated remodeling, operative mortality has been 1.5% for elective procedures. With suture annuloplasty, 10-year freedom from reoperation is 95%, even without suture annuloplasty 20-year freedom from reoperation is 85%. In our experience, root remodeling has been a valid form of valve-preserving surgery with low morbidity and mortality and excellent long-term results.
PubMed: 37554714
DOI: 10.21037/acs-2023-avs2-12 -
Circulation Research Feb 2024Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline...
BACKGROUND
Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined.
METHODS
Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription-polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA-fluorescence in situ hybridization, and Western blotting.
RESULTS
CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction-induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT mice alleviated cardiac dilation and dysfunction.
CONCLUSIONS
CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.
Topics: Animals; Humans; Mice; Adenosine Triphosphate; Aldehyde Dehydrogenase, Mitochondrial; Cardiomyopathy, Dilated; Down-Regulation; In Situ Hybridization, Fluorescence; Mice, Knockout; Mitochondria, Heart; Myocytes, Cardiac; RNA, Long Noncoding
PubMed: 38299365
DOI: 10.1161/CIRCRESAHA.123.323428 -
Nature Sep 2023Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive...
Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.
Topics: Anhydrides; Data Analysis; Diffusion; Protein Subunits; TRPV Cation Channels; Microscopy, Atomic Force; Molecular Targeted Therapy; Cryoelectron Microscopy; Protein Structure, Quaternary; Protein Multimerization
PubMed: 37648856
DOI: 10.1038/s41586-023-06470-1 -
Annual Review of Medicine Jan 2024Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases... (Review)
Review
Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.
Topics: Humans; Cardiomyopathy, Dilated; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Mutation; Heart Failure
PubMed: 37788487
DOI: 10.1146/annurev-med-052422-020535