Cardiology Commons^™

Understanding Of Metals Dysregulation In Patients With Systolic And Diastolic Dysfunction In Ischemic Heart Disease, Noman Khan, Satwat Hashmi, Amna Jabbar Siddiqui, Sabiha Farooq, Shahid Ahmed Sami, Nageeb Basir, Syeda Saira Bokhari, Hasanat Sharif, Sanaullah Junejo, Hesham R. El-Seedi, Syed Ghulam Musharraf

Department of Biological & Biomedical Sciences

Ischemic heart disease (IHD) is the leading cause of death and chronic disability in the world. IHD affects both the systolic and diastolic function of the heart which progressively leads to heart failure; a structural and functional impairment of filling or ejection of blood from the heart. In this study, the progression of systolic and diastolic dysfunction characterized according to their echocardiographic parameters including left ventricular ejection fraction (EF), grades of diastolic dysfunction and ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), were correlated with differential regulation of various metals in patients sera samples (n …

The Evolving Management Of Aortic Valve Disease: Trends In The Utilization And Cost Of Savr, Tavr, And Medical Therapy, Andrew Goldsweig

Theses & Dissertations

Aortic stenosis (AS) and regurgitation (AR) may be treated with surgical aortic valve replacement (SAVR), transcatheter AVR (TAVR), or medical therapy (MT). Data are lacking regarding usage and cost of SAVR, TAVR, and MT for patients hospitalized with aortic valve disease. From the Nationwide Readmissions Database, we determined utilization and cost trends for SAVR, TAVR, and MT in patients with aortic valve disease admitted 2012-2016 for valve replacement, heart failure, unstable angina, non-ST-elevation myocardial infarction, or syncope. From 2012 through 2016, there was a 48.1% increase in the number of patients hospitalized for aortic valve disease annually. Overall, 19.9%, 6.7%, …

Regenerative Medicine Therapy: Adipose Derived Extracellular Vesicles In Viral Myocarditis, David Gorelov, Damian N. Di Florio, Gary R. Salomon, Angita Jain, Nick E. Saikaili, Danielle J. Beetler, Swikriti Shrestha, Ming Tian, Joy Wolfram Phd, Delisa Fairweather Phd, Katelyn Bruno Phd, Judith D. Ochrietor Phd

Showcase of Osprey Advancements in Research and Scholarship (SOARS)

Objective: Myocarditis, inflammation of the heart muscle, is an autoimmune heart disease that can be caused by viruses, bacteria and toxins. Myocarditis can lead to dilated cardiomyopathy (DCM) and heart failure. Currently there are no disease-specific therapies for treating myocarditis or preventing progression to DCM. Adipose Extracellular Vesicles (AEVs) are lipid bilayer nanoparticles that are released into the outside environment of adipocytes and provide promising regenerative potential for inflammatory diseases like myocarditis.

Methods: Lipoaspirate was obtained from women and men and AEVs isolated from the lipoaspirate using tangential flow filtration. We injected wild type male BALB/c mice with 250uL AEVs …

The Role Of Mitochondrial Pyruvate Carrier 1 (Mpc1) In Heart Failure And Its Implications For Cardiac Recovery, Obadiah Issachar Kirk

Mahurin Honors College Capstone Experience/Thesis Projects

Heart failure (HF) is a complex syndrome with high mortality rates around the world. HF also has diverse etiology as many things contribute such as hypertension, obesity, coronary artery disease, inflammation, and cardiac arrhythmias. Studies have shown that unloading of a failing heart with a left ventricular assist device (LVAD) can lead to cardiac recovery in a subpopulation of individuals with advanced HF. RNA-sequencing and protein expression analysis of myocardial tissue from HF patients who underwent the LVAD implant and heart transplant indicated that subpopulation of HF patients who responded to LVAD unloading had significantly lower levels of mitochondrial pyruvate …

Biomarkers Of Inflammation In Heart Failure Patients With Reduced And Preserved Ejection Fractions: Multi-Ethnic Study Of Atherosclerosis, Michelle Lynne Stone

UNF Graduate Theses and Dissertations

Purpose Examine the relationships between high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor-α receptor-1 (sTNF-R1) and the cumulative risk of heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fractions in a diverse, population-based sample. Methods Study sample included 6,814 adult (45-84 years of age) men and women who participated in the Multi-Ethnic Study of Atherosclerosis and were free of cardiovascular disease at baseline. Cox regression was used to calculate the hazard ratios (HR) associated with elevated baseline hs-CRP (> 3-10 mg/L), IL-6 (> 75^th percentile) and sTNF-R1 (> 75^th percentile) and risk of overall …

Fingolimod Plays Role In Attenuation Of Myocardial Injury Related To Experimental Model Of Cardiac Arrest And Extracorporeal Life Support Resuscitation, Naseer Ahmed, Abid Laghari, Bashar Albkhoor, Sobia Tabassum, Sultan Ayoub Meo, Nazeer Muhammad, Daniele Linardi, Abeer A. Al-Masri, Guido Fumagalli, Giovanni Battista Luciani, Giuseppe Faggian, Alessio Rungatscher

Department of Biological & Biomedical Sciences

Background: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation.
Methods: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated …

Changes In Ventricular Depolarisation Vectors During Exercise Caused By Regional Myocardial Ischaemia, Cameruddin Vellani, Satwat Hashmi, Sadia Mahmud, Mohammad Yusuf, Safia Awan, Khawar Kazmi

Section of Cardiology

Research at the Aga Khan University for several years has been directed to find a reliable, low-cost, portable, non-invasive method for identification of coronary artery disease, its location and extent. A new method has been devised to measure the magnitude and direction of cardiac electrical vectors in three perpendicular planes during physical exercise to identify reduction in myocardial excitability as the electrophysiological marker of hypoxia. This report shows that changes in electrical forces due to exercise-induced regional hypoxia serve as indicators of reversible myocardial ischaemia. Changes in the magnitude and direction of vectors at stages of the Bruce protocol were …

Mechanisms Of Simvastatin Myotoxicity: The Role Of Autophagy Flux Inhibition., Arya Emami, Shahla Shojaei, Simone C. Da Silva Rosa, Mahmoud Aghaei, Ehsan Samiei, Amir Reza Vosoughi, Forouh Kalantari, Philip Kawalec, James Thliveris, Pawan Sharma, Amir A. Zeki, Mohsen Akbari, Joseph W. Gordon, Saeid Ghavami

Center for Translational Medicine Faculty Papers

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in both 2-dimensional (2D) and 3-dimensional (3D) cell culture, we investigated the mechanisms of simvastatin's myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited …

Phospholipases D: Making Sense Of Redundancy And Duplication, Andrew J. Morris

Internal Medicine Faculty Publications

Why have two genes when one would suffice? Evolutionary pressure means that biology, unlike government, is generally intolerant of wasted effort. Therefore, when multiple genes exist presumably they are there to provide some benefit to the organism even if that benefit is not immediately obvious to us scientists. A recent report from Raghu and colleagues (Biosci. Rep. (2018) 38, pii: BSR20181690) [1] sheds some light on one possible reason for the existence of two Phospholipases D genes in chordates when only one is present in invertebrates.

Hdl Subclass Proteomic Analysis And Functional Implication Of Protein Dynamic Change During Hdl Maturation, Yuling Zhang, Scott M. Gordon, Hang Xi, Seungbum Choi, Merlin Abner Paz, Runlu Sun, William Yang, Jason Saredy, Mohsin Khan, Alan Thomas Remaley, Jing-Feng Wang, Xiaofeng Yang, Hong Wang

Saha Cardiovascular Research Center Faculty Publications

Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven …

Atrial Fibrillation And Exercise: Exercise Recommendations, Paul Sorace, Peter Ronai, Robert Berry

Exercise Science Faculty Publications

Atrial fibrillation (AF), characterized by a rapid pulse rate and an irregular heart rhythm. It is a more common cardiac arrhythmia. AF may lack symptoms, although fatigue and an impaired exercise ability are common symptoms. This column will discuss exercise testing and training recommendations as well as special considerations.

One Amino Acid Change Of Angiotensin Ii Diminishes Its Effects On Abdominal Aortic Aneurysm, Ya Wang, Yinchuan Xu, Congqing Wu, Hongguang Xia, Yingchao Wang, Jinliang Nan, Jinghai Chen, Hong Yu, Wei Zhu, Peng Shi, Alan Daugherty, Hong S. Lu, Jian'an Wang

Saha Cardiovascular Research Center Faculty Publications

Angiotensin (Ang) A is formed by the decarboxylation of the N terminal residue of AngII. The present study determined whether this one amino acid change impacted effects of AngII on abdominal aortic aneurysm (AAA) formation in mice. Computational analyses implicated that AngA had comparable binding affinity to both AngII type 1 and 2 receptors as AngII. To compare effects of these two octapeptides in vivo, male low-density lipoprotein receptor (Ldlr) or apolipoprotein E (Apoe) deficient mice were infused with either AngII or AngA (1 μg/kg/min) for 4 weeks. While AngII infusion induced AAA consistently in …

Dennd5b Regulates Intestinal Triglyceride Absorption And Body Mass, Scott M. Gordon, Edward B. Neufeld, Zhihong Yang, Milton Pryor, Lita A. Freeman, Xiao Fan, Iftikhar J. Kullo, Leslie G. Biesecker, Alan T. Remaley

Saha Cardiovascular Research Center Faculty Publications

Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5b^−/− mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In …

Adipose-Derived Autotaxin Regulates Inflammation And Steatosis Associated With Diet-Induced Obesity, J. Anthony Brandon, Maria Kraemer, Julia Vandra, Suchismita Halder, Margo F. Ubele, Andrew J. Morris, Susan S. Smyth

Gill Heart & Vascular Institute Faculty Publications

Autotaxin (ATX) is a secreted enzyme that generates the bioactive lipid lysophosphatidic acid (LPA). We generated mice with global inducible post-natal inactivation or adipose-specific loss of the Enpp2 gene encoding ATX. The animals are phenotypically unremarkable and exhibit differences in adipocyte size and adipose tissue expression of inflammatory genes after high fat feeding without gross differences in fat distribution or body mass. Surprisingly, both models of Enpp2- deficiency exhibited marked protection from high fat diet-induced hepatic steatosis. This phenotype was not associated with differences in dietary fat absorption but may be accounted for by differences in hepatic expression of …

Antisense Oligonucleotides Targeting Angiotensinogen: Insights From Animal Studies, Chia-Hua Wu, Ya Wang, Murong Ma, Adam E. Mullick, Rosanne M. Crooke, Mark J. Graham, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly evolving therapeutic approach. The scope of the research findings not only opens doors for potentially new therapeutics of hypertension and many other diseases, but also provides insights into understanding critical physiological and pathophysiological roles mediated by AGT.

Macrophage-Derived Netrin-1 Promotes Abdominal Aortic Aneurysm Formation By Activating Mmp3 In Vascular Smooth Muscle Cells, Tarik Hadi, Ludovic Boytard, Michele Silvestro, Dornazsadat Alebrahim, Samson Jacob, Jordyn Feinstein, Krista Barone, Wes Spiro, Susan Hutchison, Russell Simon, Debra L. Rateri, Florence Pinet, David Fenyo, Mark Adelman, Kathryn J. Moore, Holger K. Eltzschig, Alan Daugherty, Bhama Ramkhelawon

Physiology Faculty Publications

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) …

Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data., Patrick J. Trainor

Electronic Theses and Dissertations

Metabolomics, the study of small molecules in biological systems, has enjoyed great success in enabling researchers to examine disease-associated metabolic dysregulation and has been utilized for the discovery biomarkers of disease and phenotypic states. In spite of recent technological advances in the analytical platforms utilized in metabolomics and the proliferation of tools for the analysis of metabolomics data, significant challenges in metabolomics data analyses remain. In this dissertation, we present three of these challenges and Bayesian methodological solutions for each. In the first part we develop a new methodology to serve a basis for making higher order inferences in metabolomics, …

Lipid Phosphate Phosphatase 3 Regulates Adipocyte Sphingolipid Synthesis, But Not Developmental Adipogenesis Or Diet-Induced Obesity In Mice, Lorenzo Frederico, Liping Yang, Jason Brandon, Manikandan Panchatcharam, Hongmei Ren, Paul Mueller, Manjula Sunkara, Diana Escalante-Alcalde, Andrew J. Morris, Susan S. Smyth

Gill Heart & Vascular Institute Faculty Publications

Dephosphorylation of phosphatidic acid (PA) is the penultimate step in triglyceride synthesis. Adipocytes express soluble intracellular PA-specific phosphatases (Lipins) and broader specificity membrane-associated lipid phosphate phosphatases (LPPs) that can also dephosphorylate PA. Inactivation of lipin1 causes lipodystrophy in mice due to defective developmental adipogenesis. Triglyceride synthesis is diminished but not ablated by inactivation of lipin1 in differentiated adipocytes implicating other PA phosphatases in this process. To investigate the possible role of LPPs in adipocyte lipid metabolism and signaling we made mice with adipocyte-targeted inactivation of LPP3 encoded by the Plpp3(Ppap2b) gene. Adipocyte LPP3 deficiency resulted in blunted …

Study Of Early After Depolarization In A Complex Human Cardiac Cell Model In Tissue, Abouzar Kaboudian, Yanyan Claire Ji, Elizabeth M. Cherry, Flavio H. Fenton

Biology and Medicine Through Mathematics Conference

No abstract provided.

Acute Pressor Response To Psychosocial Stress Is Dependent On Endothelium‐Derived Endothelin‐1, Brandon M. Fox, Bryan K. Becker, Analia S. Loria, Kelly A. Hyndman, Chunhua Jin, Hannah Clark, Robin Johns, Masashi Yanagisawa, David M. Pollock, Jennifer S. Pollock

Pharmacology and Nutritional Sciences Faculty Publications

Background

Acute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.

Methods and Results

Adult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in …

Rad Gtpase Deletion Atenuates Post-Ischemic Cardiac Dysfunction And Remodeling, Janet R. Manning, Lakshman Chelvarajan, Bryana R. Levitan, Catherine Nicole Kaminski Withers, Prabhakara R. Nagareddy, Christopher M. Haggerty, Brandon K. Fornwalt, Erhe Gao, Himi Tripathi, Ahmed Abdel-Latif, Douglas A. Andres, Jonathan Satin

Physiology Faculty Publications

The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca²⁺ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of …

Infection Of A Ventricular Septal Defect Patch With Acremonium Species, Nosheen Nasir, Kauser Jabeen, Joveria Farooqi, Binish Arif Sultan, Afia Zafar, Aamir Hameed Khan, Muneer Amanullah, Farheen Ali

Section of Internal Medicine

A ventricular septal defect (VSD) patch infection with Acremonium species isolated from vegetation and blood culture is described. Antifungal treatment was discontinued after 3 months and patient developed relapse. Surgery with prolonged oral voriconazole was instituted with recovery. We emphasize importance of surgery and prolonged therapy to treat such infections.

Quantum Confined Peptide Assemblies With Tunable Visible To Near-Infrared Spectral Range, Kai Tao, Zhen Fan, Leming Sun, Pandeeswar Makam, Zhen Tian, Mark Ruegsegger, Shira Shaham-Niv, Derek Hansford, Ruth Aizen, Zui Pan, Scott Galster, Jianjie Ma, Fan Yuan, Mingsu Si, Songnan Qu, Mingjun Zhang, Ehud Gazit, Junbai Li

Faculty & Staff Scholarship

Quantum confined materials have been extensively studied for photoluminescent applica- tions. Due to intrinsic limitations of low biocompatibility and challenging modulation, the utilization of conventional inorganic quantum confined photoluminescent materials in bio- imaging and bio-machine interface faces critical restrictions. Here, we present aromatic cyclo-dipeptides that dimerize into quantum dots, which serve as building blocks to further self-assemble into quantum confined supramolecular structures with diverse morphologies and photoluminescence properties. Especially, the emission can be tuned from the visible region to the near-infrared region (420 nm to 820 nm) by modulating the self-assembly process. Moreover, no obvious cytotoxic effect is observed for …

Acute Effects Of Diets Rich In Almonds And Walnuts On Endothelial Function, Ravindra Bhardwaj, Harvinder Dod, Manjinder S. Sandhu, Rohil Bedi, Sachin Dod, Gregory Konat, H.K. Chopra, Rakesh Sharma, Abnash C. Jain, Navin Nanda

Faculty & Staff Scholarship

Objective: Omega-3 fatty acids, especially alpha-linolenic acid (ALA), which are present in nuts may reduce cardiovascular disease (CVD) risk, by changing vascular inflammation and improving endothelial dysfunction. The objective of the study was to evaluate the acute effects of two different diets, one containing walnuts and the other almonds on endothelial function.

Methods: Twenty-seven overweight volunteers underwent a randomized 2-period, crossover, controlled intervention study. The subjects were given either walnut or almond diets which varied in monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) content. The walnut diet provided 23.1% energy from PUFA and the almond diet provided 7.6% …

Patient-Specific Quantification Of The Relationship Between The Left Atrium Pressure And The Ostial Diameter Of The Left Atrial Appendage, Sky Tianqi Gao

Electronic Theses and Dissertations

The left atrial appendage has been a historically understudied region of the heart until fairly recently with the new understanding of its role in the stroke pathway of patients with atrial fibrillation. The goal of this study is to take a look at the biomechanical behavior of the left atrium and left atrial appendage under normal physiological loading conditions using material properties taken from biaxial stretch tests. Several different options for material properties models were tested and biaxial stretch test data of cadaveric human tissue samples for the left atrium and appendage were fit to a Fung-type strain-energy function for …

Serum Tumor Necrosis Factor-Alpha Associates With Myocardial Oxygen Demand And Exercise Tolerance In Postmenopausal Women, Stephen J. Carter, David R. Bryan, William H. Neumeier, Stephen P. Glasser, Gary R. Hunter

Internal Medicine Faculty Publications

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO_2max). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest …

Role Of Sex Chromosomes In Sexual Dimorphism Of Angii-Induced Abdominal Aortic Aneurysms, Yasir Alsiraj

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role …

Tfpiα Interacts With Fva And Fxa To Inhibit Prothrombinase During The Initiation Of Coagulation, Jeremy P. Wood, Helle H. Petersen, Bingke Yu, Xiaoai Wu, Ida Hilden, Alan E. Mast

Gill Heart & Vascular Institute Faculty Publications

Tissue factor pathway inhibitor α (TFPIα) inhibits prothrombinase, the thrombin-generating complex of factor Xa (FXa) and factor Va (FVa), during the initiation of coagulation. This inhibition requires binding of a conserved basic region within TFPIα to a conserved acidic region in FXa-activated and platelet-released FVa. In this study, the contribution of interactions between TFPIα and the FXa active site and FVa heavy chain to prothrombinase inhibition were examined to further define the inhibitory biochemistry. Removal of FXa active site binding by mutation or by deletion of the second Kunitz domain (K2) of TFPIα produced 17- or 34-fold weaker prothrombinase inhibition, …

Structural Insights Into The Potency Of Sk Channel Positive Modulators, Young-Woo Nam, Razan Orfali, Tingting Liu, Kunqian Yu, Meng Cui, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca2+-activated K+ (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin. In this study, we took advantage of four compounds with potencies varying over three orders of magnitude, including 1-EBIO, NS309, SKS-11 (6-bromo-5-methyl-1H-indole-2,3-dione-3-oxime) and …

Ventricular Depolarisation Vectors In Exercise Induced Myocardial Ischaemia, Cameruddin W. Vellani, Mohammad Yusuf, Sadia Mahmud, Satwat Hashmi

Section of Cardiology

Ischaemia reduces membrane excitability and conduction of myocardial depolarisation. This would alter the synergy of electromotive forces that contribute to a resultant force at any instant. Changes in magnitude and direction of resultant forces are reflected in electrocardiographic signals. Here we show a method for obtaining the coordinates of resultant electrical forces during exercise derived from a bipolar orthogonal lead system for calculation of electrical vectors in three planes. In a trial, analysis of changes in vectors indicated that the extent of reduction in magnitude with exercise was significantly greater in groups of patients categorized by impaired effort tolerance and …