Publications by authors named "Frederick Ehlert"
Article Synopsis
- Orthotopic transcatheter tricuspid valve replacement (TTVR) devices are effective in treating tricuspid regurgitation (TR) and have gained attention after the first device received commercial approval.
- Studies show that about 35% of patients undergoing TTVR have preexisting cardiac implantable electronic device (CIED) leads, which may become entrapped during the procedure, raising concerns about safety.
- A consensus document outlines the patient demographics concerning CIED lead-related TR, evaluates the risks of lead entrapment versus transvenous lead extraction, and suggests that a specialized electrophysiologist be included in the treatment team for better decision-making.
Article Synopsis
- This study investigates how COVID-19 affects the corrected QT interval (QTc) on ECGs, noting that critical illness and inflammatory responses like those from the virus could lead to QTc prolongation.* -
- Conducted at Columbia University Medical Center with 3050 patients, the research analyzed various treatment groups over 5 days to see differences in QTc prolongation among those with and without COVID-19.* -
- Results show that patients with COVID-19 experienced a significant increase in QTc, with a modeled mean increase of 27.32 milliseconds, while those without the virus showed no significant change.*
Article Synopsis
- COVID-19 is linked to cardiovascular issues, with a study analyzing 1,029 hospitalized patients revealing that 8% had atrial arrhythmia (AA), a heart rhythm disorder confirmed through various diagnostic methods.
- Among those with AA, there were significant mortality rates, with 65% of AA patients dying, compared to only 21% of those without AA.
- Key factors that predicted higher mortality in AA patients included older age, being male, use of azithromycin, and elevated D-dimer levels.
Article Synopsis
- Cardiovascular issues are common in COVID-19 patients and significantly increase the risk of death; diagnostic studies might help identify those at higher risk.
- An analysis of 887 COVID-19 patients revealed that 63% survived without mechanical ventilation, while 23% died; notable ECG findings included atrial fibrillation in 5% and ST-T wave changes in 38%.
- Factors like elevated cardiac troponin levels, older age, and specific heart rhythm abnormalities (like AF/AFL) were linked to a higher mortality rate, emphasizing the need for targeted cardiac assessments at admission.*
Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.
J Cardiovasc Electrophysiol
December 2020
Article Synopsis
- The study examined electrocardiographic characteristics and mortality related to COVID-19 in hospitalized patients at three New York City hospitals, focusing on racial and ethnic minorities.
- Out of 1,258 screened patients, 133 died, with a significant portion being male (55.6%) and from minority backgrounds (69.9%), and most having cardiovascular conditions.
- Common arrhythmic deaths were linked to factors like age, coronary artery disease, asthma, and specific electrocardiographic abnormalities, with many patients receiving only comfort care before death.
Article Synopsis
- The study aimed to determine if analyzing vital signs alongside ECG readings can better predict outcomes for COVID-19 patients.
- Data from 1,258 adults was collected in New York hospitals early in the pandemic, focusing on deaths and ventilation needs within 48 hours of diagnosis.
- Findings showed that specific ECG abnormalities correlated with worse outcomes, suggesting that combining these findings with respiratory vitals can improve early identification of patients at higher risk for deterioration.
Article Synopsis
- * Molecular modeling indicated that the chemical structure of nalfurafine allows for stronger interactions with KOR compared to 42B, while both compounds show similar effects in relieving pain and itch in mice without causing conditioned place aversion (CPA).
- * However, 42B led to motor incoordination and reduced activity in mice, highlighting the complexity of the relationship between biochemical activity and behavioral outcomes, and indicating that different
Article Synopsis
- The COVID-19 pandemic significantly impacted cardiac electrophysiology practices, with a shortage of real-world examples for practitioners during this crisis.
- In an observational case series conducted in New York City, 29 inpatient consultations were analyzed during a period when 80% of hospital beds were occupied by COVID-19 patients.
- The study found that the majority of patients consulted were COVID-positive, with most issues managed remotely, highlighting the need for adapted workflows in response to pandemics.
Article Synopsis
- * Recommendations include practical steps for managing procedures and care while minimizing exposure risk and optimizing resource use.
- * Insights from four EP sections in a major New York City hospital highlight the importance of collaboration and adaptability in overcoming staffing and workflow challenges during the pandemic.
Article Synopsis
- The COVID-19 pandemic, starting in early 2020, has led to over 74,000 deaths worldwide and significantly impacted daily life, the economy, and healthcare systems, particularly in places like New York City.
- The disease is caused by the highly contagious SARS-CoV-2 virus, which may lead to serious heart-related issues (electrophysiologic sequelae) due to infections and treatments involving certain medications.
- To adapt to the crisis, electrophysiology departments have altered protocols by focusing on urgent procedures, extending operation hours, minimizing in-person contact, using telemedicine, and holding daily discussions to tackle clinical and ethical challenges during the pandemic.
Article Synopsis
- G protein-coupled receptors (GPCRs) can activate different signaling pathways by interacting with G proteins or β-arrestin, and certain agonists can favor one pathway over the other—this is known as "ligand bias."
- This bias in receptor signaling may be useful for developing GPCR-targeted therapies that are more precise in their effects.
- The chapter elaborates on a method for estimating the activity of weak partial agonists and provides a step-by-step guide for calculating signaling bias when measuring their effects.
Article Synopsis
- * Agonist bias is when an agonist favors one signaling pathway over another, enhancing the activation of specific proteins and pathways.
- * Understanding and quantifying agonist bias can help identify more selective therapeutic agents, offering insights into both beneficial and adverse effects of drugs.
Article Synopsis
- Two distinct cAMP signaling compartments exist in human airway smooth muscle cells, one involving β-adrenergic receptor AC6 and the other involving E prostanoid receptor AC2, and different phosphodiesterase (PDE) isozymes regulate these pathways.
- PDE8A, a cAMP-degrading enzyme, is expressed highly in these cells and its knockdown results in increased cAMP responses, particularly enhancing the response of AC6.
- Inhibiting PDE8 with a selective drug boosts cAMP levels and affects cell proliferation, presenting PDE8 as a potential therapeutic target for managing respiratory diseases like asthma and COPD.
Article Synopsis
- A new method is introduced for estimating how ligands (molecules that bind to receptors) interact with both active and inactive states of G protein-coupled receptors (GPCRs) through measuring signaling responses.
- The method involves analyzing data from a wild type GPCR and a mutant version to assess ligand affinities, isomerization constants, and signaling pathway sensitivity, giving insights into receptor behavior.
- Validation was achieved through simulations, analytical proofs, and analyzing existing data, offering improved assessments of structure-activity relationships and measures of agonist bias in receptor studies.
Article Synopsis
- Controversy in pharmacology often stems from misunderstandings of different analysis levels, leading to misinterpretations of models.
- Zhang and Kavana criticized my two-state model for allosterism for lacking cooperativity, despite evidence in my previous work showing that it can yield specific cooperativity values.
- I clarify how the two-state model relates to the cooperativity parameter (α) within the allosteric ternary complex model through receptor-state and receptor-population analysis.
Article Synopsis
- * Efficacy and observed affinity, which are commonly used, can be influenced by external factors like G proteins and signaling proteins, while receptor state affinity constants offer a cleaner measurement by assessing active and inactive receptor states directly.
- * Recent advancements allow researchers to estimate these receptor state affinity constants, enhancing our understanding of drug interactions, structure-activity relationships, and phenomena like allosterism and biased signaling.
Article Synopsis
- Researchers identified biased κ opioid receptor (KOP receptor) agonists but lacked a comprehensive study on their functional selectivity at human and mouse receptors.
- The study examined over 20 KOP receptor agonists in mouse neuroblastoma cells to assess their effects on G protein activation and receptor internalization, using specific quantification methods.
- Findings revealed significant species differences in the functional selectivity of certain agonists, with some being biased towards internalization or G protein activation depending on whether they interacted with mouse or human receptors.
Article Synopsis
- Seven transmembrane receptors, initially defined by their connection to G proteins, can now interact with a wider range of partners, including βarrestins, leading to efforts to develop selective ligands.
- These "biased" ligands can preferentially activate specific signaling pathways within the receptor, but existing analysis methods can struggle when the ligands show extreme bias in their effects.
- The article introduces a new "competitive" model for quantifying ligand bias, demonstrating its effectiveness through simulations and experiments with κ opioid receptor agonists, providing a better approach for analyzing highly biased partial agonists.
A kinetic model of GPCRs: analysis of G protein activity, occupancy, coupling and receptor-state affinity constants.
J Recept Signal Transduct Res
August 2016
Article Synopsis
- G protein-coupled receptors play a crucial role in various physiological functions by facilitating the exchange of GDP for GTP in G proteins when a ligand binds to them.* -
- We developed a kinetic model using differential equations to simulate how different factors like ligand concentration and G protein ratios affect G protein activation and receptor interactions.* -
- Our findings reveal that G protein activation can result in either a decrease or increase in receptor-G protein coupling, and we can estimate ligand affinity constants effectively, which is important for researching receptor-G protein interactions.*
International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.
Arthur Christopoulos Jean-Pierre Changeux William A Catterall Doriano Fabbro Thomas P Burris Frederick J Ehlert
Pharmacol Rev
October 2014
Article Synopsis
- Allosteric interactions are crucial for metabolic functions and signaling and have gained attention in pharmacology for developing selective drugs and research tools.
- These interactions extend beyond traditional enzyme studies, now including small molecule modulators for various receptor types, such as ion channels and hormone receptors.
- The article covers the concept of allostery in receptors, methods for identifying these interactions, and guidelines for naming and categorizing allosteric ligands.
Article Synopsis
- The study introduces a method to estimate the affinity constants of ligands for the active and inactive states of receptors, crucial for understanding signaling activation.
- The approach analyzes downstream signaling responses of G protein-coupled receptors, considering factors like allosteric modulation and receptor inactivation, while also estimating various receptor parameters.
- Results validate the method as consistent across different receptor pathways, offering a way to quantify interactions and predict ligand affinities from concentration-response data, benefiting future research in this area.
Article Synopsis
- Researchers examined how changing conserved aspartic acids to asparagine in the M1-M4 muscarinic receptors affects the binding of two chemical compounds, acetylcholine mustard and BR384.
- The D2.50N mutation increased the affinity of acetylcholine mustard and BR384 for M2-M4 receptors but had minimal impact on the rate of binding, while the D3.32N mutation significantly reduced the binding rate for acetylcholine mustard, though it also lowered BR384’s binding.
- When both mutations were combined, there was a greater decrease in the binding rate for BR384 compared to the wild type and single mutations, indicating that both compounds interact with different receptor residues and the mutations influence this interaction significantly
What ligand-gated ion channels can tell us about the allosteric regulation of G protein-coupled receptors.
Prog Mol Biol Transl Sci
June 2014
Article Synopsis
- - The GABA(A) receptor is influenced by allosteric drugs like benzodiazepines and anesthetics, which affect its response to agonists based on a consistent two-state model of receptor activity.
- - Research on etomidate, an allosteric agonist, reveals that the unliganded GABA(A) receptor has a gating constant around 10(-4), enabling a better understanding of its function.
- - In contrast to the GABA(A) receptor, allosteric interactions at the M(2) muscarinic receptor show inconsistencies with the two-state model, implying a more complex mechanism involving modulation at a peripheral binding site.
Article Synopsis
- Agonists activate G protein-coupled receptors (GPCRs), leading to a signaling response that can be studied at various levels, including the downstream effects and receptor activity.
- The active state of the receptors has a higher affinity for the agonist compared to the inactive state, and measuring the amount of agonist needed for half-maximal activation provides the observed affinity constant (K(obs)).
- The report describes a method to estimate the agonist's affinity constant for the active state (K(b)) in relation to another agonist using global nonlinear regression analysis in Prism software, which also determines the efficacy of the agonist.