Transcatheter Valve Replacement in Severe Tricuspid Regurgitation.

BACKGROUND: Severe tricuspid regurgitation is associated with disabling symptoms and an increased risk of death. Data regarding outcomes after percutaneous transcatheter tricuspid-valve replacement are needed. METHODS: In this international, multicenter trial, we randomly assigned 400 patients with severe symptomatic tricuspid regurgitation in a 2:1 ratio to undergo either transcatheter tricuspid-valve replacement and medical therapy (valve-replacement group) or medical therapy alone (control group). The hierarchical composite primary outcome was death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, an improvement of at least 10 points in the score on the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS), an improvement of at least one New York Heart Association (NYHA) functional class, and an improvement of at least 30 m on the 6-minute walk distance. A win ratio was calculated for the primary outcome by comparing all possible patient pairs, starting with the first event in the hierarchy. RESULTS: A total of 267 patients were assigned to the valve-replacement group and 133 to the control group. At 1 year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001). In comparisons of patient pairs, those in the valve-replacement group had more wins than the control group with respect to death from any cause (14.8% vs. 12.5%), postindex tricuspid-valve intervention (3.2% vs. 0.6%), and improvement in the KCCQ-OS score (23.1% vs. 6.0%), NYHA class (10.2% vs. 0.8%), and 6-minute walk distance (1.1% vs. 0.9%). The valve-replacement group had fewer wins than the control group with respect to the annualized rate of hospitalization for heart failure (9.7% vs. 10.0%). Severe bleeding occurred in 15.4% of the valve-replacement group and in 5.3% of the control group (P = 0.003); new permanent pacemakers were implanted in 17.4% and 2.3%, respectively (P<0.001). CONCLUSIONS: For patients with severe tricuspid regurgitation, transcatheter tricuspid-valve replacement was superior to medical therapy alone for the primary composite outcome, driven primarily by improvements in symptoms and quality of life. (Funded by Edwards Lifesciences; TRISCEND II ClinicalTrials.gov number, NCT04482062.).

Contemporary Outcomes and Trends for the Transseptal Mitral Valve-in-Valve Procedure Using Balloon Expandable Transcatheter Valves in the United States.

BACKGROUND: Previous transcatheter valve therapy registry analyses of transcatheter mitral valve in valve (MViV) replacement of degenerated bioprosthesis reported early experience in the United States. Given recent increases in transseptal MViV volumes and introduction of the SAPIEN 3 Ultra valve, it is important to determine contemporary outcomes for patients undergoing transseptal SAPIEN 3/SAPIEN 3 Ultra MViV replacement. METHODS: The Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy Registry was used to extract data for all patients undergoing transseptal SAPIEN 3/SAPIEN 3 Ultra MViV from 2015 to September 2022. Primary efficacy outcome was 1-year all-cause mortality. Secondary end points included 30-day mortality, functional class, quality of life, and mitral valve performance. Primary safety outcomes were device success and in-hospital complications. RESULTS: A total of 4243 patients with a mean STS score of 9.2±7.7 underwent transseptal MViV at 455 sites. The rate of Mitral Valve Academic Research Consortium technical (96.6%) success was high, and procedural complications were low. All-cause in-hospital, 30-day, and 1-year mortality rates were 3.2%, 4.3%, and 13.4%, respectively. Significant improvements in New York Heart Association class (New York Heart Association I/II, 18% to 87%) and quality of life (Kansas City Cardiomyopathy Questionnaire score, 38 to 78) were noted at 1 year (P<0.0001 for both) after MViV. Upon stratifying by STS scores, it was observed that the low-risk group (STS<4) had a significantly lower in-hospital mortality rate of 0.4%, whereas the intermediate-risk group (STS, 4-8) had an in-hospital mortality rate of 1.9%. From 2015 to 2022, the number of transseptal MViV cases/year increased significantly, whereas procedure times, length of stay, and intensive care unit hours shortened significantly. At the same time, there was a significant trend toward reduced in-hospital (P=0.0005), 30-day (P=0.004), and 1-year mortality rates (P=0.01). CONCLUSIONS: This multicenter, prospective study reports excellent procedural outcomes, 1-year mortality rates, and a significant improvement in quality of life for patients undergoing transseptal MViV in the contemporary era. Patients in the low-risk and intermediate-risk STS score categories had significantly better outcomes compared with those in the high-risk category. MViV is a reasonable therapy for the majority of patients with degenerated bioprosthetic mitral valves, who are anatomical candidates.

Transcatheter aortic valve implantation in patients with high-risk symptomatic native aortic regurgitation (ALIGN-AR): a prospective, multicentre, single-arm study.

BACKGROUND: Surgery remains the only recommended intervention for patients with native aortic regurgitation. A transcatheter therapy to treat patients at high risk for mortality and complications with surgical aortic valve replacement represents an unmet need. Commercial transcatheter heart valves in pure aortic regurgitation are hampered by unacceptable rates of embolisation and paravalvular regurgitation. The Trilogy transcatheter heart valve (JenaValve Technology, Irvine, CA, USA) provides a treatment option for these patients. We report outcomes with transfemoral transcatheter aortic valve implantation (TAVI) in patients with pure aortic regurgitation using this dedicated transcatheter heart valve. METHODS: The ALIGN-AR trial is a prospective, multicentre, single-arm study. We recruited symptomatic patients (aged ≥18 years) with moderate-to-severe or severe aortic regurgitation at high risk for mortality and complications after surgical aortic valve replacement at 20 US sites for treatment with the Trilogy transcatheter heart valve. The 30-day composite primary safety endpoint was compared for non-inferiority with a prespecified performance goal of 40·5%. The primary efficacy endpoint was 1-year all-cause mortality compared for non-inferiority with a performance goal of 25%. This trial is registered with ClinicalTrials.gov, NCT04415047, and is ongoing. FINDINGS: Between June 8, 2018, and Aug 29, 2022, we screened 346 patients. We excluded 166 (48%) patients and enrolled 180 (52%) patients with symptomatic aortic regurgitation deemed high risk by the heart team and independent screening committee assessments. The mean age of the study population was 75·5 years (SD 10·8), and 85 (47%) were female, 95 (53%) were male, and 131 (73%) were White. Technical success was achieved in 171 (95%) patients. At 30 days, four (2%) deaths, two (1%) disabling strokes, and two (1%) non-disabling strokes occurred. Using standard Valve Academic Research Consortium-2 definitions, the primary safety endpoint was achieved, with events occurring in 48 (27% [97·5% CI 19·2-34·0]) patients (pnon-inferiority<0·0001), with new pacemaker implantation in 36 (24%) patients. The primary efficacy endpoint was achieved, with mortality in 14 (7·8% [3·3-12·3]) patients at 1 year (pnon-inferiority<0·0001). INTERPRETATION: This study shows the safety and effectiveness of treating native aortic regurgitation using a dedicated transcatheter heart valve to treat patients with symptomatic moderate-to-severe or severe aortic regurgitation who are at high risk for mortality or complications after surgical aortic valve replacement. The observed short-term clinical and haemodynamic outcomes are promising as are signs of left ventricular remodelling, but long-term follow-up is necessary. FUNDING: JenaValve Technology.

MicroRNA-615-3p decreases apo B expression in human liver cells.

Plasma lipids are mainly carried in apolipoprotein B (apoB) containing lipoproteins. High levels of these lipoproteins are associated with several metabolic diseases and lowering their plasma levels is associated with reduced incidence of atherosclerotic cardiovascular disease. MicroRNAs (miRs) are small non-coding RNAs that reduce the protein expression of their target mRNAs and are potential therapeutic agents. Here, we identified a novel miR-615-3p that interacts with human 3'-UTR of apoB mRNA, induces post-transcriptional mRNA degradation, and reduces cellular and secreted apoB100 in human hepatoma Huh-7 cells. Reducing cellular miR-615-3p levels by CRISPR-sgRNA increased cellular and secreted apoB100 indicating endogenous miR regulates apoB expression. Overexpression of miR-615-3p along with or without palmitic acid treatment decreased cellular and media apoB and increased cellular triglyceride levels without inducing endoplasmic reticulum stress. These studies have identified miR-615-3p as a negative regulator of apoB expression in human liver-derived cells. It is likely that there are more miRs that regulate apoB-containing lipoprotein assembly and secretion. Discovery of additional miRs may uncover novel mechanisms that control lipoprotein assembly and secretion.

Transfemoral tricuspid valve replacement and one-year outcomes: the TRISCEND study.

BACKGROUND AND AIMS: For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes. METHODS: The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year. RESULTS: Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III-IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart Association class I or II was achieved in 93.3% (P < .001), Kansas City Cardiomyopathy Questionnaire score increased by 25.7 points (P < .001), and six-minute walk distance increased by 56.2 m (P < .001). All-cause mortality was 9.1%, and 10.2% of patients were hospitalized for heart failure. CONCLUSIONS: In an elderly, highly comorbid population with ≥moderate TR, patients receiving transfemoral EVOQUE transcatheter TV replacement had sustained TR reduction, significant increases in stroke volume and cardiac output, and high survival and low hospitalization rates with improved clinical, functional, and quality-of-life outcomes to one year. Funded by Edwards Lifesciences, TRISCEND ClinicalTrials.gov number, NCT04221490.

Novel efficacious microRNA-30c analogs reduce apolipoprotein B secretion in human hepatoma and primary hepatocyte cells.

High plasma lipid levels have been demonstrated to increase cardiovascular disease risk. Despite advances in treatments to decrease plasma lipids, additional therapeutics are still needed because many people are intolerant or nonresponsive to these therapies. We previously showed that increasing cellular levels of microRNA-30c (miR-30c) using viral vectors or liposomes reduces plasma lipids and atherosclerosis. In this study, we aimed to synthesize potent miR-30c analogs that can be delivered to hepatoma cells without the aid of viral vectors and lipid emulsions. We hypothesized that modification of the passenger strand of miR-30c would increase the stability of miR-30c and augment its delivery to liver cells. Here, we report the successful synthesis of a series of miR-30c analogs by using different chemically modified nucleosides. In these analogs, we left the active sense strand untouched so that its biological activity remained unaltered, and we modified the passenger strand of miR-30c to enhance the stability and uptake of miR-30c by hepatoma cells through phosphorothiorate linkages and the addition of GalNAc. We show that these analogs significantly reduced apolipoprotein B secretion in Huh-7 human hepatoma cells and human primary hepatocytes without affecting apolipoprotein A1 secretion and cellular lipid levels. Our results provide a proof of concept that the passenger strand of miR-30c can be modified to increase its stability and delivery to cells while retaining the potency of the sense strand. We anticipate these miR-30c analogs will be useful in the development of more efficacious analogs for the treatment of hyperlipidemias and cardiovascular diseases.

ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex.

Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer's disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer's disease.

Association of ACEI/ARB and statin prescribing patterns with mortality after Transcatheter Aortic Valve Replacement (TAVR): Findings from real-world claims data.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become the standard of care for most patients with severe aortic stenosis (AS), but the impact of medical therapy prescribing patterns on post-TAVR patients has not been thoroughly investigated. METHODS: We analyzed Optum claims data from 9,012 adults who received TAVR for AS (January 2014-December 2018). Pharmacy claims data were used to identify patients who filled ACEI/ARB and/or statin prescriptions during the study's 90-day landmark period post-TAVR. Kaplan-Meier and adjusted Cox Proportional Hazards models were used to evaluate the association of prescribing patterns with mortality during the 3-year follow-up period. Subgroup analyses were performed to examine the impact of 11 potential confounders on the observed associations. RESULTS: A significantly lower adjusted 3-year mortality was observed for patients with post-TAVR prescription for ACEI/ARBs (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.74-0.91, P = .0003) and statins (HR = 0.85, 95% CI 0.77-0.94, P = .0018) compared to patients who did not fill prescriptions for these medications post-TAVR. Subgroup analyses revealed that the survival benefit associated with ACEI/ARB prescription was not affected by any of the potential confounding variables, except preoperative ACEI/ARB prescription was associated with significantly lower risk of mortality vs postoperative prescription only. No other subgroup variables had significant interactions associated with survival benefits, including preoperative use of statins. CONCLUSIONS: In this large-scale, real-world analysis of patients undergoing TAVR, the prescription of ACEI/ARB and statins was associated with a significantly lower risk of mortality at 3-years, especially in those where the medications were initiated preoperatively.

Modulations of functional traits of Spinacia oleracea plants exposed to cadmium stress by using H2S as an antidote: a regulatory mechanism.

The present study is based on the application of H2S as an exogenous antidote in Spinacia oleracea (spinach) plants grown in Cd-contaminated (50 ppm) soil. The different doses of H2S in the form of NaHS (10, 50, 100, 200, and 500 µM) have been applied as a foliar spray to regulate the physiological attributes under Cd toxicity. Over to control, the plants grown in Cd alone showed a reduction in the fresh biomass by 48% with more production of oxidative biomarkers (H2O2, SOR, and MDA content) and antioxidative enzymes (SOD, POD, APX, and GR). Further, with the exogenous application of H2S, among all the doses the fresh biomass was found to be maximally increased at 100 µM dose by 76%, and the Cd content was reduced significantly by 25% in the shoot compared to plants grown in Cd treated soil alone. With the decrease in Cd content in the shoot, the production of H2O2, SOR, and MDA content was reduced by 52%, 40%, and 38% respectively, at 100 µM compared to the plants grown in Cd-treated soil. The activities of estimated antioxidative enzymes showed a reduction in their activities up to 100 µM. Whereas, Glutathione reductase (GR) and Phytochelatins (PCs) showed different trends with their higher values in plants treated with NaHS in the presence of Cd. At 100 µM the GR and PCs, respectively showed 48% and 37% increment over Cd-treated plants alone. At this dose, the relative expression of SOD, POD, APX, GR, and PCS5 (Phytochelatin synthetase enzyme) genes, and other functional activities (SEM and fluorescence kinetics) supported the best performance of plants at 100 µM. Therefore, among all the doses, 100 µM dose of H2S has significantly reduced the Cd toxicity by maintaining the growth and other functional traits of plants. The correlation analysis also supported the result by showing a relationship between H2S application and Cd uptake. So, with this strategy, the plants grown in metal-contaminated fields can be improved qualitatively as well as quantitatively. With further experimentation, the mode of application could be explored to increase its efficiency and to promote this strategy at a wider scale. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01389-3.

Treatment of Bicuspid Aortic Valve Stenosis with TAVR: Filling Knowledge Gaps Towards Reducing Complications.

PURPOSE OF REVIEW: Bicuspid aortic valve (BAV) disease is the most common congenital heart defect worldwide. When severe, symptomatic aortic stenosis ensues, the treatment has increasingly become transcatheter aortic valve replacement (TAVR). The purpose of this review is to identify BAV classification and imaging methods, outline TAVR outcomes in BAV anatomy, and discuss how computational modeling can enhance TAVR treatment in BAV patients. RECENT FINDINGS: TAVR use in BAV patients, when compared to use in tricuspid aortic valves, showed lower device success rate, and there remains no long-term randomized trial data. It has been reported that BAV patients with severe calcification increase the rate of complications. Additionally, the asymmetrical morphology of BAVs often results in asymmetric stent geometries which have implications for increased thrombosis risk and decreased durability. These adverse outcomes are currently very difficult to predict from routine pre-procedural imaging alone. Recently developed patient specific experimental and computational techniques have the potential to assist in filling knowledge gaps in the mechanisms of these complications and provide more information during preclinical planning for better TAVR selection in low surgical risk BAV patients. Efficacy of TAVR for irregular BAV anatomies remains concerning due to the lack of a long-term randomized trial data, their increased rate of short-term complications, and signs that long-term durability could be an issue. More knowledge on identifying which BAV anatomies are at greater risk for these adverse outcomes can potentially improve patient selection for TAVR versus SAVR in low surgical risk BAV patients.

SCAI publications committee manual of standard operating procedures.

Evidence-based recommendations for clinical practice are intended to help health care providers and patients make decisions, minimize inappropriate practice variation, promote effective resource use, improve clinical outcomes, and direct future research. The Society for Cardiovascular Angiography and Interventions (SCAI) has been engaged in the creation and dissemination of clinical guidance documents since the 1990s. These documents are a cornerstone of the society's education, advocacy, and quality improvement initiatives. The publications committee is charged with oversight of SCAI's clinical documents program and has created this manual of standard operating procedures to ensure consistency, methodological rigor, and transparency in the development and endorsement of the society's documents. The manual is intended for use by the publications committee, document writing groups, external collaborators, SCAI representatives, peer reviewers, and anyone seeking information about the SCAI documents program.

Nitrogen/sulfur-co-doped carbon quantum dots: a biocompatible material for the selective detection of picric acid in aqueous solution and living cells.

Here, a fast and eco-friendly one-pot hydrothermal technique is utilized for the synthesis of nitrogen/sulfur-co-doped fluorescent carbon quantum dots (NS-CQDs) from a simple precursor of citric acid (CA) and thiosemicarbazide (TSC). The obtained NS-CQDs exhibited strong blue emission under UV light, with fluorescence quantum yield (QY) of ~37.8%. The Commission internationale de l'eclairage (CIE) coordinates originated at (0.15, 0.07), which confirmed the blue fluorescence of the synthesized NS-CQDs. Interestingly, the prepared NS-CQDs were successfully used as a selective nanoprobe for the monitoring of environmentally hazardous explosive picric acid (PA) in different nitro- and non-nitro-aromatic derivatives of PA. The mechanism of the NS-CQDs was also explored, and was posited to occur via the fluorescence resonance electron transfer (FRET) process and non-fluorescent complex formation. Importantly, this system possesses excellent biocompatibility and low cytotoxicity in HeLa cervical cancer cells; hence, it can potentially be used for PA detection in analytical, environmental, and pathological applications. Furthermore, the practical applicability of the proposed sensing system to pond water demonstrated the feasibility of our system along with good recovery. Graphical abstract.

Highly fluorescent carbon dots from wheat bran as a novel drug delivery system for bacterial inhibition.

In this study, we prepared carbon dots (CDs) from wheat bran via hydrothermal treatment at 180°C for 3 h. The prepared CDs showed blue-green fluorescence under UV light. The fluorescence emission study of the CDs revealed that they showed maximum fluorescence emission at 500 nm. The prepared CDs showed a high quantum yield of 33.23%. Solvent-dependent fluorescence emission analysis of the CDs was performed to study the variation in fluorescence emission characteristics with solvent polarity. The prepared CDs were conjugated with amoxicillin (AMX) to explore its potential for use as a drug delivery agent for AMX. The drug release profile of the CD-AMX conjugates was analyzed at different pH (5.0, 6.8 and 7.2) to study drug release kinetics. CD-AMX conjugates showed notable bacterial inhibition against Gram-positive (S. aureus) and Gram-negative (E. coli) strains with minimal cytotoxic effects, indicating its potential as a promising antibacterial drug delivery system.

The m6A methyltransferase Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology in haploid yeast cells.

N6-Methyladenosine (m6A) is among the most common modifications in eukaryotic mRNA. The role of yeast m6A methyltransferase, Ime4, in meiosis and sporulation in diploid strains is very well studied, but its role in haploid strains has remained unknown. Here, with the help of an immunoblotting strategy and Ime4-GFP protein localization studies, we establish the physiological role of Ime4 in haploid cells. Our data showed that Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology through the long-chain fatty acyl-CoA synthetase Faa1, independently of the RNA methylation complex (MIS complex). The MIS complex consists of the Ime4, Mum2, and Slz1 proteins. Our affinity enrichment strategy (methylated RNA immunoprecipitation assays) using m6A polyclonal antibodies coupled with mRNA isolation, quantitative real-time PCR, and standard PCR analyses confirmed the presence of m6A-modified FAA1 transcripts in haploid yeast cells. The term "epitranscriptional regulation" encompasses the RNA modification-mediated regulation of genes. Moreover, we demonstrate that the Aft2 transcription factor up-regulates FAA1 expression. Because the m6A methylation machinery is fundamentally conserved throughout eukaryotes, our findings will help advance the rapidly emerging field of RNA epitranscriptomics. The metabolic link identified here between m6A methylation and triacylglycerol metabolism via the Ime4 protein provides new insights into lipid metabolism and the pathophysiology of lipid-related metabolic disorders, such as obesity. Because the yeast vacuole is an analogue of the mammalian lysosome, our findings pave the way to better understand the role of m6A methylation in lysosome-related functions and diseases.

The m6A methyltransferase Ime4 and mitochondrial functions in yeast.

In eukaryotes, the precise transcriptional and post-transcriptional regulations of gene expression are crucial for the developmental processes. More than 100 types of post-transcriptional RNA modifications have been identified in eukaryotes. The deposition of N6-methyladenosine (m6A) into mRNA is among the most common post-transcriptional RNA modifications known in eukaryotes. It has been reported that m6A RNA modification can regulate gene expression. The role of yeast m6A methyltransferase (Ime4) in meiosis and sporulation in diploid cells is very well proven, but its physiological role in haploid cells has remained unknown until recently. Previously, we have shown that Ime4 epitranscriptionally regulates triacylglycerol (TAG) metabolism and vacuolar morphology in haploid cells. Mitochondrial dysfunction leads to TAG accumulation as lipid droplets (LDs) in the cells; besides, LDs are physically connected to the mitochondria. As of now there are no reports on the role of Ime4 in mitochondrial biology. Here we report the important role played by Ime4 in the mitochondrial morphology and functions in Saccharomyces cerevisiae. The confocal microscopic analysis showed that IME4 gene deletion causes mitochondrial fragmentation; besides, the ime4Δ cells showed a significant decrease in cytochrome c oxidase and citrate synthase activities compared to the wild-type cells. IME4 gene deletion causes mitochondrial dysfunction, and it will be interesting to find out the target genes of Ime4 related to the mitochondrial biology. The determination of the role of Ime4 and its targets in mitochondrial biology could probably help in formulating potential cures for the mitochondria-linked rare genetic disorders.

The role of yeast m6A methyltransferase in peroxisomal fatty acid oxidation.

The precise and controlled regulation of gene expression at transcriptional and post-transcriptional levels is crucial for the eukaryotic cell survival and functions. In eukaryotes, more than 100 types of post-transcriptional RNA modifications have been identified. The N6-methyladenosine (m6A) modification in mRNA is among the most common post-transcriptional RNA modifications known in eukaryotic organisms, and the m6A RNA modification can regulate gene expression. The role of yeast m6A methyltransferase (Ime4) in meiosis, sporulation, triacylglycerol metabolism, vacuolar morphology, and mitochondrial functions has been reported. Stress triggers triacylglycerol accumulation as lipid droplets. Lipid droplets are physically connected to the different organelles such as endoplasmic reticulum, mitochondria, and peroxisomes. However, the physiological relevance of these physical interactions remains poorly understood. In yeast, peroxisome is the sole site of fatty acid ß-oxidation. The metabolic status of the cell readily governs the number and physiological function of peroxisomes. Under low-glucose or stationary-phase conditions, peroxisome biogenesis and proliferation increase in the cells. Therefore, we hypothesized a possible role of Ime4 in the peroxisomal functions. There is no report on the role of Ime4 in peroxisomal biology. Here, we report that IME4 gene deletion causes peroxisomal dysfunction under stationary-phase conditions in Saccharomyces cerevisiae; besides, the ime4Δ cells showed a significant decrease in the expression of the key genes involved in peroxisomal ß-oxidation compared to the wild-type cells. Therefore, identification and determination of the target genes of Ime4 that are directly involved in the peroxisomal biogenesis, morphology, and functions will pave the way to better understand the role of m6A methylation in peroxisomal biology.

Causes and hemodynamic findings in chronic severe pulmonary regurgitation.

Severe pulmonary regurgitation (PR) most commonly occurs as a sequelae of treatment of pulmonic stenosis or Tetralogy of Fallot with fewer cases of primary pulmonic valvular regurgitation. The amount of PR is influenced by valvular integrity, right ventricular (RV) size, and RV diastolic pressures. In chronic severe PR, the RV remodels to accommodate the regurgitant flow and RV stroke volume increases to maintain effective forward blood flow. Hemodynamic changes include a widened pulmonary artery (PA) pulse pressure and low PA diastolic pressures. As the amount of regurgitation increases, RV end diastolic pressure becomes elevated and systemic cardiac output is reduced, especially with exercise. "Ventricularization" of the PA pressure tracing, in which the contour of the PA pressure is similar to the contour of the RV pressure, is a specific but not sensitive finding in severe PR. © 2015 Wiley Periodicals, Inc.

Watchman in ascending aorta for systemic protection (WAASP): Novel use of Watchman in ascending aorta for embolic protection-first in man.

We report two cases where left atrial appendage closure (LAA) with Watchman was successfully performed despite presence of definite LAA thrombus. Because there was the risk of thrombus dislodgement, we transiently placed an additional Watchman device in the ascending aorta for embolic protection. © 2017 Wiley Periodicals, Inc.

Misregulation of a DDHD Domain-containing Lipase Causes Mitochondrial Dysfunction in Yeast.

The DDHD domain-containing proteins, which belong to the intracellular phospholipase A1 (iPLA1) family, have been predicted to be involved in phospholipid metabolism, lipid trafficking, membrane turnover, and signaling. Defective cardiolipin (CL), phosphatidylethanolamine, and phosphatidylglycerol remodeling cause Barth syndrome and mitochondrial dysfunction. Here, we report that Yor022c is a Ddl1 (DDHD domain-containing lipase 1) that hydrolyzes CL, phosphatidylethanolamine, and phosphatidylglycerol. Ddl1 has been implicated in the remodeling of mitochondrial phospholipids and CL degradation. Our data also suggested that the accumulation of monolysocardiolipin is deleterious to the cells. We show that Aft1 and Aft2 transcription factors antagonistically regulate the DDL1 gene. This study reveals that the misregulation of DDL1 by Aft1/2 transcription factors alters CL metabolism and causes mitochondrial dysfunction in the cells. In humans, mutations in the DDHD1 and DDHD2 genes cause specific types of hereditary spastic paraplegia (SPG28 and SPG54, respectively), and the yeast DDL1-defective strain produces similar phenotypes of hereditary spastic paraplegia (mitochondrial dysfunction and defects in lipid metabolism). Therefore, the DDL1-defective strain could be a good model system for understanding hereditary spastic paraplegia.

Post-TAVR aortogram: Transform it into a modern tool for prognosis and efficiency.

Video densitometry after aortography can provide objective assessment of aortic regurgitation post-transcatheter aortic valve replacement (TAVR) Contrast density ratio between the left ventricular outflow track and proximal aorta (LVOT-AR) of >0.17 suggests greater than mild aortic insufficiency and correlates with echo findings LVOT-AR of >0.17 is associated with higher 30-day and 1-year mortality.