Converting Enzyme Research Articles

Generation of a SARS-CoV-2-susceptible mouse model using adenovirus vector expressing human angiotensin-converting enzyme 2 driven by an elongation factor 1α promoter with leftward orientation

IntroductionTo analyze the molecular pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a small animal model such as mice is needed: human angiotensin converting enzyme 2 (hACE2), the receptor of SARS-CoV-2, needs to be expressed in the respiratory tract of mice.MethodsWe conferred SARS-CoV-2 susceptibility in mice by using an adenoviral vector expressing hACE2 driven by an elongation factor 1α (EF1α) promoter with a leftward orientation.ResultsIn this model, severe pneumonia like human COVID-19 was observed in SARS-CoV-2-infected mice, which was confirmed by dramatic infiltration of inflammatory cells in the lung with efficient viral replication. An early circulating strain of SARS-CoV-2 caused the most severe weight loss when compared to SARS-CoV-2 variants such as Alpha, Beta and Gamma, although histopathological findings, viral replication, and cytokine expression characteristics were comparableDiscussionWe found that a distinct proteome of an early circulating strain infected lung characterized by elevated complement activation and blood coagulation, which were mild in other variants, can contribute to disease severity. Unraveling the specificity of early circulating SARS-CoV-2 strains is important in elucidating the origin of the pandemic.

QSAR Modeling of Substituted Benzimidazole Derivative as Angiotensin II-AT1 Receptor Antagonist: WHIM Descriptors

Selective inhibition of Angiotensin II (Ang II) is an important strategy for design of Ang II-AT1 receptor antagonist which is devoid of the common side effects of angiotensin converting enzyme inhibitors (ACEIs). QSAR study of 4, 5, 6, and 7 substituted benzimidazole analogs were performed using Dragon 2.1 (Milano Chemometrics) for antagonism of Ang II. The study was carried out on 33 compounds; mathematical models were obtained by means of the sequential multiple linear regression analysis (SMLR). QSAR analysis have produced good predictive models and give statistically significant correlations of selective Ang II antagonism with WHIM descriptors concerning size, symmetry, shape and distribution of molecules atom. The predictive ability of the resulting QSAR model was evaluated by cross validated correlation coefficient (q2 = 0.659). It was able to describe more than 68% of the variance in the experimental activity. This QSAR study helps in design and prediction of Ang II inhibitory activity of novel substituted benzimidazole Ang II-AT1 receptor antagonist.

Stable Biotherapeutic Penetration Screening in Critically Small Colorectal Metastatic Cancer Biopsies Allows for Oncolytic Virus‐Delivered Chemotherapeutic Response Assessment through 3D Bioprinted Organoid Expansion

AbstractOncolytic viral‐delivered chemotherapeutics have exciting potential for metastatic cancer therapies, including colorectal cancer, but require advanced screening systems for better patient prediction. We optimized primary metastatic colorectal tumor processing and 3D (3‐dimensional) bioprinted tumors to prove efficacy as long‐term screening systems. Normally, this time period would use animals, but we show it is possible to gain useful data in vitro before preclinical stages, to reduce animal modeling and give better clinical trial predictions. Liver tumors were collected from 12 colorectal cancer patients, evaluated for expansion, 3D bioprinted, and tested for ability to create long‐term organoid models with screening of oncolytic viral‐loaded FCU1 enzyme conversion of 5‐fluorocytosine (5‐FC) into the highly toxic 5‐fluorouracil (5‐FU). Donated tumor size was the limiting factor. 75% of patients could be used for screening of viral delivery. Response between patients was overall positive, with good secondary tumor development, outer active cellular content and inner necrotic core. Oncolytic challenge shows good screening potential and cellular targeting, demonstrating an added bystander effect, optimizing the low‐dose. Stable long‐term metastatic organoid models were made, lasting many months, with potential for retesting rather than one‐off analysis. Oncolytic virus‐delivered chemotherapy is promising and warrants further investigation for metastatic colorectal cancers.

Genetic polymorphisms influencing antihypertensive drug responses.

Hypertension is a major contributor to cardiovascular disease and its associated morbidity and mortality. The low efficacy observed with some anti-hypertensive therapies has been attributed partly to inter-individual genetic variability. This paper reviews the major findings regarding these genetic variabilities that modulate responses to anti-hypertensive therapies such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, calcium channel blockers (CCBs) and β-adrenoceptor blockers. The importance of studying these genetic polymorphisms stems from the goal to optimise anti-hypertensive therapy for each individual patient, aiming for the highest efficacy and lowest risk of adverse effects. It is important to recognise that environmental and epigenetic factors can contribute to the observed variations in drug responses. Owing to the multigenic and multifactorial nature of drug responses, further research is crucial for translating these findings into clinical practice and the establishment of reliable recommendations.

BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications.

Diacylglycerol kinase ζ is a positive insulin secretion regulator in pancreatic β-cell line MIN6

Some isoforms of diacylglycerol (DAG) kinase (DGK), an enzyme converting DAG into phosphatidic acid, i.e., DGKα, γ and δ, have been reportedly involved in the regulation of pancreatic β-cell function. DGKζ has also been reported to be expressed in rat pancreatic β-cells. However, its function in pancreatic β-cells remains unknown. The present study aimed to elucidate the function of DGKζ in pancreatic β-cells. The expression of DGKζ was detected in the β-cell line MIN6B and mouse pancreatic islets and in the cytoplasmic fraction from MIN6B cells. The knockdown of DGKζ with siRNA significantly decreased glucose-induced insulin secretion in MIN6B cells. The induction of DGKζ expression in MIN6CEon1 cells with a doxycycline-inducible stable expression system significantly increased glucose-induced insulin secretion. In contrast, glucose-induced insulin secretion was not changed when a kinase-dead DGKζ mutant (G356D) was overexpressed in MIN6CEon1 cells, indicating that a mechanism dependent on its kinase activity mediates the facilitatory effect of DGKζ on glucose-induced insulin secretion. Additionally, we revealed that DGKζ overexpression exhibited no effect on cell cycle of MIN6 cells. These results suggest that DGKζ plays a facilitatory role in insulin secretion in pancreatic β-cells.

Cutting-edge developments in plastic biodegradation and upcycling via engineering approaches

The increasing use of plastics has resulted in the production of high quantities of plastic waste that pose a serious risk to the environment. The upcycling of plastics into value-added products offers a potential solution for resolving the plastics environmental crisis. Recently, various microorganisms and their enzymes have been identified for their ability to degrade plastics effectively. Furthermore, many investigations have revealed the application of plastic monomers as carbon sources for bio-upcycling to generate valuable materials such as biosurfactants, bioplastics, and biochemicals. With the advancement in the fields of synthetic biology and metabolic engineering, the construction of high-performance microbes and enzymes for plastic removal and bio-upcycling can be achieved. Plastic valorization can be optimized by improving uptake and conversion efficiency, engineering transporters and enzymes, metabolic pathway reconstruction, and also using a chemo-biological hybrid approach. This review focuses on engineering approaches for enhancing plastic removal and the methods of depolymerization and upcycling processes of various microplastics. Additionally, the major challenges and future perspectives for facilitating the development of a sustainable circular plastic economy are highlighted.

Enzymatic conversion of wood materials from the pulp and paper industry

The reactivity during enzymatic hydrolysis of 8 industrially produced samples of pulps and semi-chemical pulps by enzyme preparations of glycosyl hydrolases B151 and F10 produced by a strain of ascomycete fungus Penicillium verruculosum has been determined. It is shown for the first time that among fibrous pulps available on the market of pulp and paper industry in Russia, the highest level of yield of glucose from the initial wood during biocatalysis using cellulases and hemicellulases is characteristic of semi-chemical pulps obtained after cooking of hardwood with green liquor. A high degree of enzymatic conversion of softwood bleached kraft pulp has been established, which in combination with the possibility of obtaining modified polysaccharide materials from non-hydrolysable residue makes this cellulosic substrate the most promising for the development of biological processes at pulp and paper industries. It is shown that drying of pulp negatively affects the efficiency of cellulose hydrolysis, while mechanical milling improves the performance of the enzymatic saccharification process.

Frequency and progression of azotemia during acute and chronic treatment of congestive heart failure in cats.

Azotemia is common in cats with congestive heart failure (CHF) and might be exacerbated by diuretic therapy. Determine frequency, risk factors, and survival impact of progressive azotemia in cats treated for CHF. One hundred and sixteen client-owned cats with kidney function testing performed at least twice during acute or chronic CHF treatment. Serum creatinine (sCr) and electrolyte concentrations were determined at multiple clinical timepoints to detect azotemia and kidney injury (KI; sCr increase ≥0.3 mg/dL). Furosemide dosage between timepoints was calculated. Multivariable modeling was performed to identify predictors of KI, change in serum biochemistry results, and survival. Azotemia was common at all timepoints, including initial CHF diagnosis (44%). Kidney injury was documented in 66% of cats. Use of a furosemide continuous rate infusion was associated with increased risk of KI during hospitalization (odds ratio, 141.6; 95% confidence interval [CI], 12.1-6233; P = .01). Higher furosemide dosage was associated with increase in sCr during hospitalization (P = .03) and at first reevaluation (P = .01). Treatment with an angiotensin converting enzyme inhibitor was associated with fewer lifetime KI events (P = .02). Age in years was the only variable associated with shorter survival (hazard ratio, 1.1; 95% CI, 1.0-1.1; P = .03). Neither sCr nor KI were associated with long-term outcome. Azotemia and KI were common in cats during CHF treatment but did not impact survival.

The involvement of the dysfunctional insulin receptor signaling system in long COVID patients with diabetes and chronic pain and its implications for the clinical management using taVNS.

In clinical terms, chronic pain is the most prevalent sequela resulting from COVID-19, which is induced by the novel coronavirus (SARS-CoV-2), while type 2 diabetes mellitus (T2D) is the most common comorbidity. This triangular relationship can be attributed to the dysfunction of the insulin receptor signaling system (IRSS) in both central and peripheral systems. Patients with T2D are essentially more susceptible to SARS-CoV-2 infection due to the widespread expression of angiotensin converting enzyme 2 (ACE2) in their pancreatic beta cells, which serves as the cellular port for the SARS-CoV-2 to infect and enter the cell. This infection can exacerbate chronic pain and insulin resistance for various reasons. Peripherally, once infected, the virus can cause damage to peripheral nerves and pancreatic β-cells, further exacerbating pain and glucose metabolism conditions. Additionally, in the central nervous system, dysfunctional IRSS is closely linked to chronic pain. Over the past few years of the COVID-19 pandemic, an increasing body of evidence suggests that insulin and other medications currently used in clinical practice for hyperglycemia control may not be safe for treating these patients. Therefore, we need a proper approach for the treatment of chronic pain in long COVID patients, especially patients with T2D. This review presents evidence that transcutaneous auricular vagal nerve stimulation (taVNS) may provide a viable treatment option for chronic pain and metabolic dysfunction by improving the function of IRSS in both the central nervous system and peripheral tissues.

Pediatric Chronic Heart Failure: Age-Specific Considerations of Medical Therapy

Chronic heart failure (CHF) is a rare entity in children but carries a burden of high mortality and morbidity. Medical treatment of pediatric CHF is largely based on guidelines for the adult population. In contrast to adults, evidence for the efficacy of medications in treating CHF in children is sparse. This may be due to the difficulty of conducting high-powered studies in children or to true differences in the mechanisms of CHF pathophysiology. Recent observations suggest that CHF in children differs from adults at the molecular and cellular levels. Different pathways are involved, leading to less fibrosis and hypertrophy than in adults, with potential implications for therapy. The main pathophysiological goals of medical treatment of pediatric CHF due to systemic left ventricular dysfunction are discussed in this review. These include preload and afterload optimization, diminishing cardiomyocyte apoptosis and necrosis as well as interstitial fibrosis, and optimizing myocardial oxygen consumption. The pediatric myocardium should be provided with optimal conditions to achieve its regenerative potential. The cornerstones of medical CHF therapy are angiotensin converting enzyme inhibitors (ACEI), beta blockers and mineralocorticoid receptor antagonists. There are potential benefits of tissue ACEI and β1-selective beta blockers in children. Angiotensin receptor blockers are an alternative to ACEI and their slightly different mechanism of action may confer certain advantages and disadvantages. Diuretics are employed to achieve a euvolemic state. Digoxin is used more frequently in children than in adults. Promising new drugs already routinely used in adults include angiotensin receptor-neprilysin inhibitors and sodium-glucose contransporter 2 inhibitors.

Attenuation of Ampullary Anoctamin 1 by the Peritoneal Fluid in Rhesus Macaques with Spontaneous Endometriosis.

Altered peristaltic and ciliary dysfunction is a feature of females with endometriosis. To further explore this premise, we examined the ampulla of rhesus macaques (Macaca mulatta) with and without spontaneous endometriosis for the expression of adenylate kinase 7 (AK7), a mitochondrial-dwelling nucleotide converting enzyme with critical roles in cellular kinesis, forkhead protein box J1 (FOXJ1), a marker of cilia abundance, and Anoctamin 1 (ANO1) as a marker of both smooth muscle contraction and ciliogenesis. We further performed an in vitro experiment that treated ampullary segments with peritoneal fluid from animals with and without endometriosis. We report significantly downregulated expression of ANO1 in the ampulla of monkeys with endometriosis (in vivo), and in the ampullary segments exposed to peritoneal fluid of animals with endometriosis. We did not observe statistically significant differences in the expression of AK7 or FOXJ1 both in vivo and in vitro. This highlights potentially essential roles of Anoctamin 1 in the oviduct, the dampening of which may lead to a specific subtype of endometriosis-caused subfertility.

Shedding Light on MOF-Encapsulated Tandem Enzymes.

Photo-enzyme coupling system are receiving widespread attention due to the unique opportunity by integrating photochemistry with nature's enzymatic machinery. Here we highlight a recent work about MOF encapsulated tandem enzymes for photoenzymatic CO2 conversion, and provide an outlook for the further development of photo-enzyme systems for green bio-manufacturing.

Novel angiotensin-converting enzyme inhibitory peptides derived from tuna (Thunnus maccoyii): The integration of computer tools with in vitro experiments

With the rapid development of bioinformatics and the establishment of various databases for bioactive peptides, they provided a time-efficient method for discovering novel bioactive peptides from diverse protein sources. Peptides with angiotensin converting enzyme (ACE) inhibitory ability were considered potential dietary interventions for hypertension. The aim of this study was to discovery novel potential ACE inhibitory peptides from four tuna (Thunnus maccoyii) protein by the integration of computer tools with in vitro experiments. In this context, eight novel peptides were synthesized and the WHR (IC50 = 1383.2 μM) and LGR (IC50 = 115.4 μM) showed better ACE inhibitory ability. The interaction mechanism of LGR with ACE was investigated. The corresponding results showed that mixed-type was the kinetic pattern by Lineweaver-Burk plot, LGR formed ten hydrogen bonds with ACE by molecular docking and they had strong affinity by molecular dynamic simulation. Furthermore, LGR may regulate blood pressure through AKT1, MAPK1, HRAS, EGFR and SRC targets by network pharmacology predicting. Additionally, LGR exhibited excellent stability in temperature, pH and gastrointestinal digestion. Finally, the apparent permeability coefficient of LGR was measured to be 6.38 × 10−6 cm/s. These results suggested that the integration of computer tools with in vitro experiments was a promising approach to discovery novel potential bioactive peptides.

Captopril prevents depressive-like behavior in an animal model of depression by enhancing hippocampal neurogenesis via activation of the ACE2/Ang (1–7)/Mas receptor/AMPK/BDNF pathway

The brain's Renin-Angiotensin System plays an important role in the modulation of mental state. Previously we demonstrated that activated angiotensin (Ang) converting enzyme (ACE) 2, which converts Ang II into Ang (1–7), or the intracerebroventricular administration of Ang (1–7) produced an antidepressant-like effect in mice via Mas receptors (MasR). Since the ACE inhibitor Captopril (Cap) increases Ang (1–7) in the brain, it remains unknown whether Cap affects the depressive-like behavior of olfactory bulbectomized (OBX) mice, an animal model of depression. We tested the effect of Cap on the depressive-like behavior of these mice in the tail-suspension test, quantified ACE2, p-AMP activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF) using western blots, and examined the changes in Ang (1–7) level, neurogenesis, and in the expression of ACE2 and MasR on various cell types in the hippocampus using immunohistochemistry. While OBX mice exhibited a depressive-like behavior in the tail-suspension test, as well as a reduction in ACE2, Ang (1–7), p-AMPK, BDNF, and hippocampal neurogenesis, these changes were prevented by Cap administration. The intracerebroventricular administration of Ang (1–7) improved the OBX-induced depressive-like behavior. Except for the changes in ACE2 and Ang (1–7), the effects of Cap were inhibited by the coadministration of A779 (MasR inhibitor) or Compound-C (AMPK inhibitor). ACE2 localized to all cell types, while MasR localized to microglia and neurons. Our results suggest that Cap may act on ACE2-positive cells in the hippocampus to increase ACE2 expression level, thereby enhancing signaling in the ACE2/Ang (1–7)/MasR/AMPK/BDNF pathway and producing antidepressant-like effects.

Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.

Alveolar macrophages (AMs) are the first line of cellular defense in the lower airway against pathogens. However, chronic and excessive alcohol use impairs the ability of AMs to phagocytize and clear pathogens from the alveolar space, in part through dysregulated fuel metabolism and bioenergetics. Our prior work has shown that chronic ethanol (EtOH) consumption impairs mitochondrial bioenergetics and increases lactate levels in AMs. Further, we recently demonstrated that EtOH increases glutamine dependency and glutamine-dependent maximal respiration while decreasing flexibility, shifting away from pyruvate-dependent respiration and towards glutamine-dependent respiration. Glutaminolysis is an important compensatory pathway for mitochondrial respiration when pyruvate is used for lactic acid production or when other fuel sources are insufficient. Using a mouse AM cell line, MH-S cells, exposed to either no EtOH or EtOH (0.08%) for 72 h, we determined the dependency of mitochondrial respiration and bioenergetics on glutamine as a fuel source using an extracellular flux bioanalyzer. Real-time measures were done in response to bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase 1, which prevents the enzymatic conversion of glutamine to glutamate, in media vehicle or in response to vehicle alone, followed by testing mitochondrial stress. The step-by-step protocol provided herein describes our methods and calculations for analyzing average levels of glutamine-dependent basal mitochondrial respiration, mitochondrial ATP-linked respiration, maximal mitochondrial respiration, and mitochondrial spare respiratory capacity across multiple biological and experimental replicates.

Organic waste and beechwood cellulose blend saccharification and validation of hydrolysates by fermentation

This study demonstrates the sustainable advancement of fermentation media by blending the organic fraction of municipal solid waste (OFMSW) with organosolv beechwood cellulose. Investigations examined the effects of enzyme dosages and OFMSW integration into organosolv beechwood cellulose on sugar yield. The findings indicate that OFMSW inclusion and Cellic® CTec3 dosage significantly influence hydrolysis across two different batches of beechwood cellulose. Experimental data showed that OFMSW inclusion levels of 35% and 45% (w/w) produced sugar levels comparable to pure beechwood cellulose, achieving 58% to 68% (w/w) saccharification with sugar concentrations of 44 to 46 g/L. This highlights OFMSW's potential as a buffer substitute during the enzymatic conversion of organosolv cellulose. The resulting sugar-rich hydrolysates, derived from OFMSW-cellulose blends and pure cellulose, were evaluated for ethanol and cell biomass production using Saccharomyces cerevisiae and Mucor indicus, yielding 30 g of ethanol/L hydrolysate. Furthermore, OFMSW inclusion in beechwood cellulose proved to be an excellent alternative to synthetic nitrogen agents for S. cerevisiae cell production, reaching 12.2 g of biomass/L and surpassing the biomass concentration from cultivation on cellulose hydrolysate with nitrogen supplementation by threefold. However, M. indicus did not grow in the OFMSW-cellulose blend, suggesting that the inhibitory compounds of OFMSW may be a bottleneck in the proposed process. The present study demonstrates the benefits of incorporating OFMSW into cellulose material, as it enhances both cost-effectiveness and sustainability. This is attributed to the natural buffering properties and nitrogen content of OFMSW, which reduces the need for synthetic agents in fermentation-based lignocellulose biorefineries.Key points• OFMSW inclusion significantly influences beechwood cellulose saccharification.• OFMSW could be an excellent alternative for synthetic agents in biorefinery.• S. cerevisiae achieved higher biomass growth on OFMSW/cellulose mix compared to YPD.Graphical abstract

Lactylation of Hdac1 regulated by Ldh prevents the pluripotent-to-2C state conversion

BackgroundCellular metabolism regulates the pluripotency of embryonic stem cells (ESCs). Yet, how metabolism regulates the transition among different pluripotent states remains elusive. It has been shown that protein lactylation, which uses lactate, a metabolic product of glycolysis, as a substrate, plays a critical role in various biological events. Here we focused on that glycolysis regulates the conversion between ESCs and 2-cell-like cells (2CLCs) through protein lactylation.MethodsRNA-seq revealed the activation of 2-cell (2C) genes by suppression of Ldh. Stable isotope labeling by amino acids in cell culture (SILAC) coupled with lactylated peptide enrichment and quantitative mass spectrometric analysis was carried out to investigate the mechanism how protein lactylation regulates the pluripotent-to-2C transition. And we focused on Hdac1. Lactylation of Hdac1 required for silencing 2C genes was proved by quantitative reverse-transcription PCR (qRT-PCR), immunofluorescence (IF), Western blot and chimeric embryos. Chromatin immunoprecipitation coupled with sequencing (ChIP-seq) and in vitro deacetylation assay confirmed lactylation of Hdac1 promoting its binding at 2C genes and enhancing its deacetylase activity, thereby facilitating the removal of H3K27ac and the silencing of 2C genes.ResultsWe found that inhibition or depletion of Ldha, the enzyme converting pyruvate to lactate, leads to the activation of 2C genes, as well as reduced global lactylation in ESCs. To investigate the mechanism how protein lactylation regulates the pluripotent-to-2C transition, quantitative lactylome analysis was performed, and 1716 lactylated proteins were identified. We then focused on Hdac1, a histone deacetylase involved in the silencing of 2C genes. Lactylation of Hdac1 promotes its binding at 2C genes and enhances its deacetylase activity, thus facilitating the removal of H3K27ac and the silencing of 2C genes.ConclusionsIn summary, our study reveals a mechanistic link between cellular metabolism and pluripotency regulation through protein lactylation. Our research is the first time to reveal that quantitative lactylome analysis in mouse ESCs. We found that lactylated Hdac1 promotes its binding at 2C genes and enhances its deacetylase activity, thus facilitating the removal of H3K27ac and the silencing of 2C genes.

Abstract 4122247: Impact of serum chloride levels for ventricular arrhythmias in patients with heart failure undergoing cardiac resynchronization therapy

Background: As previous reports of ventricular arrhythmia (VA) as a prognostic marker of mortality in heart failure (HF) patients included those with implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) devices, little is known about the risk factors of VA among patients undergoing cardiac resynchronization therapy (CRT), especially those without previous VA. The prognostic role of electrolyte abnormalities has been highlighted in HF patients. This study evaluated the impact of serum chloride levels for VA and all-cause death in patients with HF who underwent CRT without VA before CRT implantation. Methods: From the retrospective cohort of 397 HF patients (age 63+/-13, male 74%) who undergoing CRT implantation between 2010 and 2020, this study enrolled 175 patients (82% implanted CRT with a defibrillator) without a previous history of VA (sustained ventricular tachycardia (VT) of ventricular fibrillation (VF)). We studied the impact of serum chloride levels before CRT implantation. The primary endpoint was defined as VA, VA with ICD therapy and sudden cardiac death. The secondary endpoint was all-cause mortality. Results: During median follow-up of 35 months, 53 patients (30%) experienced VA. Patients with VA had a tendency toward high LVESV (172ml vs. 150ml, p<0.09) and low left ventricular ejection fraction (26 vs. 29, p<0.09), and significantly reduced rate of angiotensin converting enzyme inhibitors or angiotensin receptor blockers (30% vs. 70%, p<0.05) at the time of CRT implantation. The rate of CRT responders was significantly higher in patients without VA than with VA (59% vs. 40%, p<0.05). The cut-off value of chloride for VA was determined to be 102mEq/l using receiver operating characteristic analysis. The patients with chloride ≤102mEq/l had significantly higher rates of VA (41% vs. 25%, log-rank p<0.05) and mortality (33% vs. 18%, log-rank p<0.05) (Figure). By multivariate cox analysis, the level of chloride had an independent predictive value of VA in patients with CRT (hazard ratio [HR] 1.08 per 1mEq/l decrease, 95% confidence interval [CI] 1.00-1.16, p<0.05) (Table). Conclusions: The chloride level had a predictive value for VA after CRT implantation in HF patients without previous VA. The management of electrolytes, including chloride, might be important for preventing fatal arrhythmia in patients with HF undergoing CRT implantation.

Abstract 4138024: Identifying the Medications with the Greatest Reduction in Mortality in Coronary Artery Dissection

Introduction: Coronary artery dissection (CD) is a potentially fatal complication, usually arising either spontaneously or iatrogenically. Therefore, identifying treatment methods that reduce mortality is of great importance. The American College of Cardiology recommendations stipulate that patients who have experienced CD may benefit from beta-blocker therapy, as beta-blockers have been shown to reduce the incidence of recurrent CD. Currently, there is little published data in support of beta-blockers providing mortality reduction for CD. Given the significant risk of mortality from CD, we aimed to test the veracity of these recommendations using a retrospective multicenter study as well as having a main objective of exploring means to lower mortality in CD. Methods: We conducted a retrospective, multicenter cohort that identified 2,104 patients diagnosed with CD. We extracted the data from across 16 West Florida hospitals in between the years of 2017-2022. Our patients were identified and stratified based on common lab values and cardioprotective medications they were taking. Chi-square and binary logistic regression was used to calculate odds ratios for mortality. The odds ratio estimate for mortality was our primary outcome with attention given to factors that were associated with an increased or decreased likelihood of mortality in patients with CD. Results: Patients on beta-blockers, angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were the only variables that were statistically significant. Out of 2,104 patients, 1,562 patients were on beta-blockers (74.2%), and 921 were on an ACEi/ARB (43.8%). Our data revealed that the odds ratio for mortality in patients with CD while on beta blockers was 0.375 (p-value 0.0009, confidence interval 0.210-0.669), and while on ACEi/ARBs was 0.447 (p-value 0.0077, confidence interval 0.247-0.808). These results indicate a significant reduction in mortality in patients who are taking beta-blockers and/or ACEi/ARB medications after being diagnosed with CD. Conclusion: Our data can be viewed as supportive of the current recommendation for the primary use of beta-blockers in patients with spontaneous CD, as well as suggesting angiotensin receptor blockers and angiotensin-converting enzyme inhibitors as possible additional therapies