Posts Tagged: reperfusion

Critical Issues for the Translation of Cardioprotection

Critical Issues for the Translation of Cardioprotection

Gerd Heusch

Lack of robust preclinical data, lack of phase II dosing and timing studies, and too loose inclusion criteria in clinical trials contribute to poor translation. Adapted from Rossello and Yellon6 with permission of the publisher. Copyright ©2016, American Heart Association, Inc. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. TIMI indicates thrombolysis in myocardial infarction. [Powerpoint File]

Molecular Basis of Cardioprotection: Signal Transduction in Ischemic Pre-, Post-, and Remote Conditioning

Molecular Basis of Cardioprotection: Signal Transduction in Ischemic Pre-, Post-, and Remote Conditioning

Gerd Heusch

Simplified scheme of cardioprotective signaling at the mitochondria. I,II,III, IV indicates respiratory chain complexes I,II,III, IV; AlDH, aldehyde dehydrogenase; Cx 43, connexin 43; CypD, cyclophilin D; ER/SR, endoplasmic/sarcoplasmic reticulum; F, F-ATPase; GSK3β, glycogen synthase kinase 3 β; HIF1α, hypoxia-inducible factor 1α; HK-2, hexokinase 2; K+, potassium ion; KATP, ATP-dependent potassium channel; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; NOS, nitric oxide synthase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; and STAT, signal transducer and activator of transcription. [Powerpoint File]

Molecular Basis of Cardioprotection: Signal Transduction in Ischemic Pre-, Post-, and Remote Conditioning

Molecular Basis of Cardioprotection: Signal Transduction in Ischemic Pre-, Post-, and Remote Conditioning

Gerd Heusch

Simplified scheme of cardioprotective signal transduction. Please note, this scheme does not entail the dimension of time, and details of mitochondrial signaling are displayed in Figure 2. Akt indicates protein kinase B; AMPK, cyclic adenosine monophosphate–activated kinase; BNP, brain natriuretic peptide; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; Cx 43, connexin 43; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; ERK, extracellular regulated kinase; FGF, fibroblast growth factor; Gs/Gi/q, stimulatory/inhibitory G protein; GPCR, G protein-coupled receptor; gp130, glycoprotein 130; GSK3β, glycogen synthase kinase 3 β; H2S, hydrogen sulfide; H11K, H11 kinase; HIF1α, hypoxia-inducible factor 1α; IGF, insulin-like growth factor; iNOS, inducible NO synthase; IP3, inositoltrisphosphate; JAK, Janus kinase; KATP, ATP-dependent potassium channel; Na+/H+, sodium/proton-exchanger; NPR, natriuretic peptide receptor; pGC, particulate guanylate cyclase; p38, mitogen-activated protein kinase p38; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; PI3K, phosphatidylinositol (4,5)-bisphosphate 3-kinase; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; PTEN, phosphatase and tensin homolog; PTK, protein tyrosin kinase; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; SR, sarcoplasmic reticulum; STAT, signal transducer and activator of transcription; and TNFα, tumor necrosis factor α. The NO/PKG pathway is displayed in green, the RISK pathway in yellow, and the SAFE pathway in red. [Powerpoint File]

Acute Coronary Syndromes Compendium: Reperfusion Strategies in Acute Coronary Syndromes


Acute Coronary Syndromes Compendium: Reperfusion Strategies in Acute Coronary Syndromes

Akshay Bagai, George D. Dangas, Gregg W. Stone, Christopher B. Granger

Patient-related and health system–related delays in ST-segment–elevation myocardial infarction. DIDO indicates door-in-door-out; and PCI, percutaneous coronary intervention. Adapted from Windecker et al28 with permission of the publisher. (Illustration Credit: Ben Smith.) [Powerpoint File]

Myocardial Conditioning: Opportunities for Clinical Translation

Myocardial Conditioning: Opportunities for Clinical Translation

Michel Ovize, Hélène Thibault, Karin Przyklenk

Current status: efficacy of cardioprotection with postconditioning and remote conditioning. For each intervention, published phase II trials were reviewed and classified as showing a significant (positive) reduction in infarct size, a trend toward a reduction in infarct size, a significant (negative) exacerbation of infarct size, or a trend toward exacerbation of infarct size in treated cohorts vs controls. For postconditioning, positive phase II trials reported that, on average, infarct size was reduced by ≈35%. For remote conditioning, positive phase II trials have shown greater variation, with reductions in infarct size ranging from ≈10% to 60% among studies (illustration credit: Ben Smith). [Powerpoint File]

Mitochondria as a Drug Target in Ischemic Heart Disease and Cardiomyopathy

Mitochondria as a Drug Target in Ischemic Heart Disease and Cardiomyopathy

Andrew M. Walters, George A. Porter Jr, Paul S. Brookes

Cardioprotective signaling: all roads lead to mitochondria. Ischemic preconditioning (IPC) either directly or indirectly (via G-protein coupled receptors or growth factor receptors) activates numerous protein kinases and other cell signaling molecules, including the generation of reactive oxygen species (ROS) for signaling purposes. These signals filter through a limited number of downstream mediators, including the following: (1) endothelial NO synthase (eNOS) generation of NO•, (2) phosphorylation and inhibition of glycogen synthase kinase-3β (GSK-3β), (3) changes in metabolism, and (4) activation of mitophagy. At the mitochondrial level, many of these signals converge on the opening of mitochondrial ATP sensitive K+ channel (mKATP) and mitochondrial BK channels, and the activation of H+ channels, both of which inhibit the PT pore directly, or inhibit the events leading up to its opening. Volatile anesthetics also trigger mitochondrial K+ channel opening and recruit many of the same kinase signals as IPC. Other drugs such as statins can also activate kinases in the reperfusion injury salvage kinase pathway. Together, these events inhibit cell death during subsequent ischemia and reperfusion (IR) injury. See text for more details. (Illustration Credit: Ben Smith.) [Powerpoint File]