Posts Tagged: precision medicine

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]

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes: Insights Into Molecular, Cellular, and Functional Phenotypes

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes: Insights Into Molecular, Cellular, and Functional Phenotypes

Ioannis Karakikes, Mohamed Ameen, Vittavat Termglinchan, Joseph C. Wu

Expression of key structural and functional genes in induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). A, Schematic of the major structural and functional features of iPSC-CMs. In adult CMs, on membrane depolarization a small amount of Ca2+ influx induced by activation of voltage-dependent L-type Ca2+ channels (CACNAC1) triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptors (ryanodine receptor 2 [RYR2]), termed Ca2+-induced Ca2+-release mechanism. The released Ca2+ ions diffuse through the cytosolic space and bind to troponin C (TNNC1), resulting in the release of inhibition induced by troponin I (TNNI3), which activates the sliding of thin and thick filaments, and lead to cardiac contraction. Recovery occurs as Ca2+ is extruded by the Na2+/Ca2+ exchanger (NCX1) and returned to the SR by the sarco(endo)plasmic Ca2+-ATPase pumps on the nonjunctional region of the SR that are regulated by phospholamban (PLN). This process is conserved in iPSC-CMs, but major differences exist, such as a nascent SR, the presence of an inositol 1,4,5-trisphosphate–releasable Ca2+ pool, and the complete absence of T-tubules. The genes encoding the major transmembrane ion channels involved in the generation of action potential are also shown. B, Immunofluorescence staining of cardiac troponin T and α-sarcomeric actinin in iPSC-CMs. C, Line-scan images and spontaneous Ca2+ transients in iPSC-CMs. ACTC1 indicates actin, α, cardiac muscle 1; CACNA1C, calcium channel, voltage-dependent, L type, α1C subunit; IPTR3, inositol 1,4,5-trisphosphate receptor, type 3; KCNH2, potassium voltage-gated channel, subfamily H (eag-related), member 2; KCNIP2, potassium channel–interacting protein 2; KCNJ2, potassium inwardly rectifying channel, subfamily J, member 2; KCNQ1, potassium voltage-gated channel, KQT-like subfamily, member 1; MYBPC3, myosin binding protein C; MYH6, myosin, heavy chain 6, α; MYH7, myosin, heavy chain 7, β; MYL2, myosin, light chain 2; MYL3, myosin, light chain 3; SCN5A, sodium channel, voltage-gated, type V, α-subunit; SERCA2, SR Ca2+-ATPase 2; TNNI3, troponin I type 3; TNNT2, troponin T type 2; TTN, titin; and TPM1, tropomyosin 1 (α). [Powerpoint File]

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes: Insights Into Molecular, Cellular, and Functional Phenotypes

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes: Insights Into Molecular, Cellular, and Functional Phenotypes

Ioannis Karakikes, Mohamed Ameen, Vittavat Termglinchan, Joseph C. Wu

Current applications of patient-specific induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) technology. iPSC-CMs have been used for disease modeling of inherited cardiomyopathies and channelopathies, regenerative therapies, drug discovery, and cardiotoxicity testing, as well as for studying metabolic abnormalities and cardiac development. [Powerpoint File]