Translational Challenges in Atrial Fibrillation

Translational Challenges in Atrial Fibrillation

Jordi Heijman, Jean-Baptiste Guichard, Dobromir Dobrev, Stanley Nattel

Photoacoustic imaging to define patient-specific atrial fibrillation mechanisms. Photoacoustic imaging uses (1) a pulsed-wave laser beam to activate endogenous (eg, water molecules, lipids, collagen) or exogenous photoabsorbing molecules, producing (2) thermal vibrations that generate (3) acoustic waves, which can be detected and localized using (4) ultrasound. Integration of photoacoustic imaging in an electrophysiology catheter in combination with intracardiac echocardiography could be used to assess ablation lesions (through endogenous chromophores) and perform in vivo Ca2+ imaging through novel cell-permeable photoacoustic Ca2+ indicators. [Powerpoint File]

Translational Challenges in Atrial Fibrillation

Translational Challenges in Atrial Fibrillation

Jordi Heijman, Jean-Baptiste Guichard, Dobromir Dobrev, Stanley Nattel

Molecular targets for atrial fibrillation (AF) therapy. Extensive work during the past 20 years has identified several molecular mechanisms in atrial cardiomyocytes and fibroblasts contributing to AF-promoting electric and structural atrial remodeling, which are potential molecular targets for AF therapy. Notable targets include ion channels involved in atrial electrophysiology (blue box), atrial Ca2+-handling and Ca2+-signaling (red box), microRNAs (miRs) inhibiting protein translation or promoting mRNA degradation (green boxes) of several targets (indicated in bold), transcription factors and gene regulatory networks (purple box), the components of the myofilaments (teal box), oxidative stress and altered metabolism (pink box), and inflammation (orange box). For all these components, there is a strong focus on targets with atrial-selective or atrial-predominant expression or atrial-selective effects (indicated with *). AMPK indicates 5′ adenosine monophosphate-activated protein kinase; Ang-II, angiotensin-II; Ang-IIR, angiotensin-II receptor; CaMKII, Ca2+/calmodulin-depenent protein kinase-II; CaN, calcineurin; CTFGR, connective tissue growth factor receptor; Cx-43, connexin-43; Dsp, desmoplakin; ERK, extracellular signal-regulated protein kinases; HDAC, histone deacetylases; ICa,L, L-type Ca2+ current; IK1, basal inward-rectifier K+ current; IK2P, 2 pore-domain K+ current; IK,ACh, acetylcholine-activated inward-rectifier K+ current; IKr, rapid delayed-rectifier K+ current; IKs, slow delayed-rectifier K+ current; IKur, ultrarapid delayed-rectifier K+ current; IL-1β, interleukin-1β; IL1R, interleukin-1 receptor; INa, Na+ current; INaK, Na+-K+-ATPase current; INCX, Na+/Ca2+-exchange current; ISK, small-conductance Ca2+-activated K+ current; Ito, transient-outward K+ current; JAK/STAT, Janus kinase/signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; MEF2, myocyte enhancer factor-2; Mito, mitochondrion; MyBP-C, myosin-binding protein-C; MYL4, atrial light chain-1; NFAT, nuclear factor of activated T-cells; NLRP3, NACHT, LRR, and PYD domain binding protein-3; nNOS, neuronal nitric oxide synthase; PDGFR, platelet-derived growth factor receptor; PITX2, paired like homeodomain-2; PKC, protein kinase C; PLB, phospholamban; RLC, myosin regulatory light chain; ROS, reactive oxygen species; RyR2, ryanodine receptor channel type-2; SERCA2a, sarcoplasmic reticulum Ca2+-ATPase type-2a; SIRT1, sirtuin-1; SLN, sarcolipin; SR, sarcoplasmic reticulum; TBX5, T-box transcription factor-5; TGF-β1, transforming growth factor-β1; TGFβR, transforming growth factor-β receptor; TnC/TnI/TnT, troponin C/I/T; and TRPC3/TRPM7, transient receptor potential channel C3/M7. [Powerpoint File]

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Peroxisomal reactive oxygen species (ROS) and metabolism. Peroxisomal ROS are produced as by-products of enzymatic reactions within β-oxidation, polyamine synthesis, d-amino acid deamination, and hypoxanthine oxidation and have been found to be key regulators of pexophagy. ACOX indicates acyl-coenzyme A (CoA) oxidases; ATM, ataxia-telangiectasia mutated; CAT, catalase; CoA, coenzyme A; DAO, d-amino acid oxidase; GPX, glutathione peroxidase; LC3, light chain 3; mTOR, mammalian target of rapamycin; PAO, polyamine oxidase; PEX, peroxin; PRDX, peroxiredoxin; SOD, superoxide dismutase; TSC1, tuberous sclerosis protein 1; ULK1, uncoordinated 51-like kinase 1; and XAO, xanthine oxidase. [Powerpoint File]

 

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Cytosolic reactive oxygen species (ROS) production and regulation of cytosolic metabolic pathways. Cytosolic ROS are formed most notably through NOX (nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) activity and influence metabolic processes including glycolysis and downstream oxidative phosphorylation, pentose phosphate pathway activity, and autophagy. ACC indicates acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ATM, ataxia-telangiectasia mutated; CAMKKβ, Ca2+/calmodulin-dependent protein kinase β; CoA, coenzyme A; CRAC, calcium release–activated channel; ER, endoplasmic reticulum; GLUT1, glucose transporter 1; HIF1α, hypoxia-inducible factor 1α; HK, hexokinase; IP3R, inositol 1,4,5-trisphosphate receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthase; OONO, peroxynitrite; OxPL, oxidized phospholipid; PDK-1, phosphoinositide-dependent kinase-1; PFK, phosphofructo kinase; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase 2; PPP, pentose phosphate pathway; STIM1, stromal interaction molecule 1; and TSC2, tuberous sclerosis protein 2. [Powerpoint File]

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Endoplasmic reticulum and reactive oxygen species (ROS). The endoplasmic reticulum (ER) is highly sensitive to redox status, and altered ROS signaling can influence protein folding, Ca2+ release, and mitochondrial respiration. ATF6 indicates activating transcription factor 6; CAMKKII, Ca2+/calmodulin-dependent protein kinase II; Cyto, cytoplasm; ER, endoplasmic reticulum; ERO1, ER oxidoreductin 1; GPX, glutathione peroxidase; GRP78, glucose-regulated protein, 78 kDa; GSH, glutathione; GSSG, glutathione disulfide; IMS, intermembrane space; IP3R, inositol 1,4,5-trisphosphate receptor; IRE1α, inositol-requiring enzyme 1α; MCU, mitochondrial calcium uniporter; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; OxPL, oxidized phospholipid; p66shc, SHC-transforming protein 1 isoform p66; PDI, protein disulfide isomerase; PERK, protein kinase R (PKR)–like endoplasmic reticulum kinase; and Prdx, peroxiredoxin [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Mural cells derived from endocardium in developing heart. A and B, Endocardial cells undergo endothelial to mesenchymal transition to form PDGFRβ+PDGFRα+NG2– mesenchymal cells in the cardiac cushion (black arrows). C and D, Mesenchymal cells migrate into myocardium (white arrows) to form PDGFRβ+PDGFRα–NG2+αSMA+ smooth muscle cells or PDGFRβ+PDGFRα–NG2+αSMA– pericytes. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Molecular regulation of endocardial cushion endothelial to mesenchymal transition (EndoMT). Multiple signaling pathways including BMP (bone morphogenetic protein), TGFβ (transforming growth factor-β), and Notch control endocardial contribution to cushion morphogenesis through regulating EndoMT. AVC indicates atrioventricular canal; Msx, msh homeobox; OFT, outflow tract; Rbpj, recombination signal binding protein for immunoglobulin kappa J region; Slug, snail family zinc finger 2; Snail, snail family zinc finger 1; and Twist, twist basic helix–loop–helix transcription factor. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Schematic showing the endocardial cell plasticity. Endocardial cell (in the center) differentiates into hematopoietic cell, cushion mesenchyme, coronary, liver vascular endothelial cell, and cardiomyocyte (arrows). Question (?) indicates that the cardiomyocyte fate needs validated. Endocardial cell also contributes to fibroblast, adipocyte, pericyte, and smooth muscle cell (dotted arrows), which might be through intermediate stage of mesenchymal cell. [Powerpoint File]

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte

Regenerative reprogramming approaches. In vivo induction of transdifferentiation can be used to repopulate the cells lost during aging as an alternative to transplantation, complementing the intrinsic regenerative capacity. For instance, neurons lost to neurodegenerative diseases can be replaced by transdifferentiating resident glia or astrocytes; cardiac fibroblasts can be the cell source for induced cardiomyocytes; α, ductal, and acinar cells can be used for β cells. Alternatively, transient 4F (OCT4, KLF4, SOX2, and c-Myc) expression can be used to rejuvenate cells. This in turn can decelerate degeneration of biological units that have low regeneration capacity (eg, aorta) or augment regeneration capacity by counteracting stem cell exhaustion (eg, muscle) or by enhancing the plasticity of organs that intrinsically undergo cell conversions during regeneration (eg, transdifferentiation in the pancreas and dedifferentiation in the kidney). MuSC indicates muscle stem cell. [Powerpoint File]

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Joshua Mayourian, Delaine K. Ceholski, David M. Gonzalez, Timothy J. Cashman, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa

Human engineered cardiac tissue (hECT) contractility assay. A, hECTs are created, cultured, and tested in a custom bioreactor with integrated force-sensing end-posts; as the tissue beats, deflections of the end-posts are tracked. Output contractile metrics include, but are not limited to, developed force (DF), maximum rates of contraction and relaxation (+/− dF/dt, respectively), and beat rate. B, Confocal microscopy of hECTs labeled with cardiac troponin I (green) and DAPI (4’,6-diamidino-2-phenylindole; blue) displays cardiomyocytes with striated sarcomeres and regions of aligned myofibrils. Inset shows magnified view of registered sarcomeres. C, hECT labeled with sarcoendoplasmic reticulum Ca2+-ATPase 2 (red) and DAPI (blue) shows sarcoplasmic reticulum structures distributed throughout the tissue. Bar = 40 µm. [Powerpoint File]

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Joshua Mayourian, Delaine K. Ceholski, David M. Gonzalez, Timothy J. Cashman, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa

Endothelial–cardiomyocyte interplay through paracrine factors. Endothelial cell NO increases basal contractility via nitrosylation of L-type Ca2+ channel (LTCC) and ryanodine receptor (RyR2). NO attenuates β-adrenergic effects on cardiomyocyte excitation–contraction coupling via cGMP-dependent degradation of cAMP and protein kinase G (PKG)-mediated decrease of LTCC activity. PKG also phosphorylates troponin I, leading to myofilament calcium desensitization and thus increased lusitropy. Endothelin-1, which mainly acts through the endothelin A (ETA) receptor in ventricular cardiomyocytes, may increase calcium entry via protein kinase C (PKC)-mediated (1) increase of LTCC activity, (2) indirect activation of sodium–calcium exchanger (NCX) reverse mode by increasing Na+–H+ exchanger activity, and (3) direct activation of NCX reverse (shown) and forward (not shown) mode. Endothelin-1 alters myofilament Ca2+ sensitivity via protein kinase C/D (PKC/D) phosphorylation of troponin I and myosin-binding protein C. Finally, endothelin-1 may increase calcium-induced calcium release via inositol trisphosphate (IP3) activation of inositol trisphosphate receptor (IP3R), which sensitizes RyR2 on the sarcoplasmic reticulum (SR). Green and red arrows denote activation and inhibition, respectively. PLB indicates phospholamban; and SERCA, sarcoendoplasmic reticulum Ca2+-ATPase. [Powerpoint File]

Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function

Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function

Tamer Sallam, Jaspreet Sandhu, Peter Tontonoz

Pipeline of long noncoding RNA (lncRNA) discovery and characterization. ASO indicates antisense oligonucleotide; ChiRP, chromatin isolation by RNA purification; qPCR, quantitative polymerase chain reaction; RAP, RNA antisense purification; and RIP, RNA immunoprecipitation. [Powerpoint File]

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift

Steven A.J. Chamuleau, Mira van der Naald, Andreu M. Climent, Adriaan O. Kraaijeveld, Kim E. Wever, Dirk J. Duncker, Francisco Fernández-Avilés, Roberto Bolli
and on behalf of the Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes (TACTICS) Group

Translational axis, with stage I studies (including in vitro studies and zebrafish models) to investigate basic mechanisms and discover new proteins and pathways; stage II studies (exploratory studies), predominantly in mouse models, to conduct hypothesis-generating research and initial in vivo testing; and stage III studies (confirmatory studies), as the last step before entering the clinical arena, involving rigorous research in a multicentre setting, with prospective registration of the key features of the study. Preclinical meta-analyses are performed with data from both exploratory and confirmatory studies, with the goal of giving an overview of available data, pointing out the gaps, and providing a guideline for future preclinical research. The level of standardization of methodology increases through the translational axis. [Powerpoint File]

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Dariush Mozaffarian, Jason H.Y. Wu

Relevant characteristics of dairy foods and selected molecular pathways potentially linked to cardiometabolic disease risk. Dairy foods are characterized by a complex mixture of nutrients and processing methods that may influence cardiovascular and metabolic pathways. Examples of relevant constituents include specific fatty acids, calcium, and probiotics. Relevant processing methods may include animal breeding and feeding, fermentation, selection and cultivation of bacterial and yeast strains (eg, as fermentation starters), and homogenization. Such modifications can alter the food’s composition (eg, fermentation leads to production of vitamin K2 from vitamin K1) and its lipid structures (eg, homogenization damages MFGM), each of which can affect downstream molecular and signaling pathways. BCSFA indicates branched-chain saturated fats; GLP-1, glucagon-like peptide 1; MCSFA, medium-chain saturated fats; MFGM, milk-fat globule membranes; MGP, matrix glutamate protein; mTOR, mammalian target of rapamycin; and OCSFA, odd-chain saturated fats. (Illustration Credit: Ben Smith.) [Powerpoint File]

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Dariush Mozaffarian, Jason H.Y. Wu

Selected cardiometabolic benefits of flavonoids and potential underlying molecular mechanisms. In vitro and animal studies support bioactivity of purified flavonoids or flavonoid-rich plant extracts across multiple tissues. Relevant molecular pathways seem to include (1) modulation of gene expression and signaling pathways. Enhancement of AMPK (5′-monophosphate-activated protein kinase) phosphorylation and activation appears to be a common mechanism affected by several types of flavonoids. Modulation of other signaling pathways has also been observed including increased expression of PPAR-γ (peroxisome proliferator-activated receptor-γ) and inhibition of NF-κB (nuclear factor-κB) activation; (2) interaction with gut microbiota. Dietary flavonoids may alter gut-microbial composition because of probiotic-like properties and stimulate growth of specific bacteria (eg, Akkermansia muciniphila) that may confer metabolic benefits. Conversely, metabolism of dietary flavonoids by gut bacteria generates downstream metabolites (eg, phenolic acids) that may possess unique properties and reach higher circulating and tissue concentrations compared with parent flavonoids, thus enhancing biological activity of flavonoids; (3) Direct flavonoid–protein interactions. Growing evidence suggests that flavonoids both stimulate and inhibit protein function, including of ion channels in the vasculature and liver and carbohydrate digestive enzymes (α-amylase and α-glucosidase) in the gastrointestinal tract. Such effects may partly contribute to regulation of vascular tone and glucose metabolism. ERK1/2 indicates extracellular signal-regulated kinases 1 and 2; GLUT4, glucose transporter type 4; IRS2, insulin receptor substrate-2; MAPK, mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PKA; protein kinase-A; SREBP-1c, sterol regulatory element–binding protein-1c; TG, triglycerides; and TLR4, toll-like receptor 4. (Illustration Credit: Ben Smith.) [Powerpoint File]