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Physiological Hypertrophy myocardial Cardiac hypertrophy ventricular mass cardiomyocyte adaptive response heart haemodinamic loads physiological stimuli post-natal developmental growth hypertension valvular insufficiency hypertrophy pathological physiological states neurohormonal factors overload mechanical burden heart stretch myocyte induction gene expression cardiac growth factors Insulin-like growth factor 1 IGF1 cardiac growth factor physiological hypertrophy IGF1 pathways developmental myocardial growth hyperplasia increase cell number postnatal growth myocardial mass normal postnatal growth injury stress signals pressure overload hypertension volume overload valvular heart diseases
pheypic endpoints quantitative effects on increasing level of constitutive proteins sarcomeric proteins gene program modulating stress signals pheypical characteristics reexpression fetal-type genes cardiac failure beta-myosin heavy chain beta-MHC atrial natriuretic peptide ANF skeletal alpha-actin SkAc interstitial fibrosis cell drop-out inadequate growth cardiac vasculature contractile dysfunction diastolic systolic glycolytic metabolism load cardiac output increasing wall thickness Law of Laplace adaptive response outcome impaired relaxation enhanced cardiac function normal sarcomeric organization a normal pattern of cardiac gene expression interstitial fibrosis cell death vessel growth molecular functional abnormalities pathological hypertrophy myocardial infarction cardiac performance aerobic exercise capacity pathological hypertrophy pathophysiological stpoint major predictor pharmacological genetic blockade pathological cardiac antihypertrophic strategies setting pathological cardiac hypertrophy insulin growth factor 1 IGF1 phosphatidyl-inositol 3-kinase PI3KAkt pathway end-diastolic volume increase ventricle contraction initial length muscle fiber sensitivity contractile proteins Ca2+ clinical physiologists enlargement output dysfunctional ventricle short-term dinamic dilatation Laplace's Law cardiology heart pathophysiology wall stress directly proportional cavity chamber diameter blood pressure wall stress pressure aortic stenosis normal stress wall thickness concentric hypertrophy load aortic mitral insufficiencies total chamber eccentric-type hypertrophy plasticity sarcomerogenesis individual myocytes sarcomeres cross-sectional area cells elongation myocyte chamber diameter pressure overload hypertrophy concentric eccentric hypertrophy volume overload progression disease pressure chamber is furr offset additional increases in wall thickness hypertrophy becomes compensating eventually manifest heart failure advanced ion hypertrophy biological process mechanical event classical biological feedback loop mechanical signal ion cardiac mass workload equilibrium signal off pathological settings Physiological cardiac hypertrophy Starling curve showing stroke volume end diastolic pressure EDP end diastolic volume EDP linear relationship causes increase stroke volume curve heart failure Laplace formula stress proportional pressure volume ventricle inversely proportional wall thickness pressure volume ventricle wall thickness hypertrophy mechanism weak producing insufficient hypertrophy resultant exuberant reaction pathological forms cardiac hypertrophy adaptive responses stress sustained overload short-term benefit long-term harm uptake oxygen metabolites removal catabolites heat accumulation adverse effects cardiac performance stroke volume contractility oxygen consumption modifications cardiac output skeletal muscle work heart rate contractility metabolic responses exercise Isotonic left internal diameter wall thickness wall thickness eccentric strength-training isometric intramuscular pressure contraction coronary capillaries plasma blood volume expansion chamber volume normal wall stress contractility cardiomyopathy Signaling pathways neurohormonal factors signaling pathways pressure overload IGF1 endolin 1 ET-1 angiotensin II Ang II isotonic exercise cardiac growth factor IGF1 Cardiac sympatic venous arterial arterial blood pressure Enhanced sympatic activity hemorrhagic shock IGF1-PI3K-Akt pathway
compensatory mechanisms Hypertrophy myocardial alterations regulation signal transduction pathways transcription factors energy metabolism signaling molecules regulating physiological hypertrophy pheype IGF1-PI3K-Akt pathway signaling molecules IGF1 insulin-like short-term metabolic effects growth factor-like long-term effects cell proliferation differentiation IGF1 tissues liver growth hormone stimulation Interaction IGF1 insulin receptor cylasmic tyrosine kinase activity phosphorylation insulin receptor specific substrates IRS Phosphorylated IRSs src homology 2 SH2 domains PI3K target cells activated PI3K functional effects IGF1 enhanced glucose transport enhanced contractility inhibition programmed cell death apoptosis IGF1 knockout KO mouse models IGF1 receptor IGF1R IGF1R insulin receptor IR PI3KAkt pathway IGF1 transgenic TG mice overexpressing IGF1R myofiber enhanced contractile function Cardiac-specific IR KO mice impaired contractile function wild type WT mice IR KO heart baseline WT 41 insulinIGF1 pathway protective effects Cardiac-specific IGF1 overexpression death fibrosis chronic coronary artery narrowing ex vivo model of ischemia perfusion short-term administration IGF1 animal studies apoptosis clinical trials IGF1 insulin pathway glucose metabolism uptake heart glycolysis glycogen fatty acid utilization PI3K lipid kinase family phosphorylation membrane phosphoinositides PIP PI3K class IA enzymes of heterodimeric complexes consisting catalytic subunit p110-alpha p110-beta p110-delta regulatory subunit p85-alpha p85-beta p55-gamma type activated tyrosine kinase receptors antigen receptors cytokine receptors class IB PI3K enzymes p110-gamma catalytic p101 regulatory subunit activated G-protein coupled receptors GPCRs class II PI3K CII-alpha CIIbeta CII-gamma tyrosine kinase receptors GPCRs integrins chemokines class III PI3K Vps34 PI3Kp110-alpha pathway stimulated receptor tyrosine kinases pathological hypertrophy GPCRinduced PI3Kp110-gamma pathway Overexpression constitutively active PI3Kp110-alpha mutant IGF1R TG mice 50 over-expressing IGF1R co-expression dominant negative PI3Kp110-alpha caPI3Kp110-gamma mutant Akt activity reactivation fetal genes PI3Kp110-alpha signaling GPCRPI3Kp110-gamma pathway PTEN Phosphatase TENsin homologue deleted chromosome 10 PI3K conversion active inositol lipids inactive PTEN KO mice PI3Kp110-alpha PI3Kp110-gamma activity cardiac function depressed negative decreased cAMP level inhibition of adenylate cyclase uncontrolled PI3Kp110-gamma activity whereas effect on cell activation PI3Kp110-alphaAkt pathway deletion PI3Kp110-gamma co-expression dnPI3Kp110- alpha upstream molecules involved activation Akt major signaling pathways protein Akt kinase PKB protein kinase B signal-transduction molecules contractile function angiogenesis Akt IGF1-PI3K-Akt physiological hypertrophy pathway serine threonine kinases I 3 isoforms Akt1-2 downstream targets modulation local responses processes metabolism cell growth differentiation survival contractile function Akt activated IGF1 insulin PI3K resultant phosphorylated PIP pleckstrin domain of Akt translocation cytosol plasma membrane Akt phosphorylation T308 phosphoinositide-dependent kinase-1 PDK1 activation Akt phosphorylated regulatory phosphorylation site S473 identification kinase putative rapamycin-insensitive complex mammalian target rapamycin mTORC2 mTOR G-beta-LmLTST8 S473 phosphorylation 54 Akt activated dnPI3K TG mice subdomains phosphorylates specific effector targets Akt re-localization cell deactivated dephosphorylation at T308 S473 protein phosphatase 2A PPA2 PH domain leucinerich repeat protein phosphatase PHLPP cardiac-specific mouse models upstream molecules in vivo TG mice specific mutations pleckstrin domain subcellular localizing signals Akt E40K mutant active form Akt T308DS473D mutant activated phosphorylation myocyte overexpression myristilated Akt Akt plasmamembrane activator PDK1 overexpression nucleartargeted non-activated Akt associated contractile function transgene overexpression tetracycline-regulated system myristilated myocardial Akt activity deletion Akt isoform isoforms Akt1 KO mice Akt2 KO insulin resistance Akt3 KO PI3Kp110-alpha PI3Ka dependent pathway transcription genes G-protein coupled receptors GPCR mitogen-activated protein kinase MAPKs pathways cAMP ion Gas G-alpha Gbg G-betagamma protein ICa calcium deletions Akt1Akt2 double- KO mice Akt1Akt3 double- KO in utero cardiomyocytic function striated muscle-specific KO mouse Akt activator PDK1 baseline hypertrophic adaptation physiological stimuli PI3K IGF1R mouse models Dn PI3K TG mice pathological stimulus pressure overload blunted response IGF1R contractio lusitropism calcium transient L-type Ca2+ channel LTCC release sarcoplasmic reticulum SR ryanodine receptor RyR Relaxation reuptake SR ATPase pump SERCA2 fine-tuning of Ca2+ LTCC blockers IcaL PTEN cardiac-specific nuclear-overexpression Akt release uptake association SERCA2 protein nuclear-targeted overexpressed Akt mutant PP1A protein level PKA activity PP1A dephosphorylate PKA phosphorylation site PLB inhibitor of SERCA2 downregulate PP1A Adrenergic signalling Catecholamines neurohumoral factors Catecholamines beta1AR beta2AR subtypes coupled Gproteins beta2AR intracellular signaling Gs Gi proteins beta1AR PI3K Volume overload total protein content pressure overload Mechanisms Akt-induced inhibition GSK-3 kinase GSK-3 shuttling transcription factors NFATs GATA-4 betacatenin eukaryotic translation initiation factor-2B epsilon eIF-2B epsilon ribosomal assembly inhibiting translation Akt GSK-independent mechanisms mammalian target rapamycin mTOR central controller cell growth complex mTOR complex 1 mTORC1 insulin-regulated complex G-beta-LmLST8 G-protein beta-subunit-like protein regulator mTOR kinase activity raptor TSC–Rheb PRAS40 phosphorylated T246 binds 14-3-3 cytosolic anchor protein PRAS40 mTOR mTOR PRAS40-induced negative regulation Active mTORC1 n phosphorylates eukaryotic initiation factor-4E eIF-4E-binding protein 4E-BP1 perm released eIF-4E mRNA 5' cap-binding protein eIF-4G scaffold protein eIF-4A ATP-dependent RNA helicase initiating cap-mRNA-dependent translation rapamycin inhibiting mTOR activation of ribosomal protein S6 kinase S6K mechanism involves S6K phosphorylation Cardiac remodeling mechanisms protein degradation FOXO forkhead box-containing protein O subfamily transcription factors negative regulators FOXO3 proteosomal degradation 1MAFbx muscle-atrophy F-box MuRF1 muscle-specific pathophysiology cardiac hypertrophy inactivation transcription target genes Phosphorylated FOXO translocated to cylasm FOXO1 FOXOs TSC2 mTOR pathway inhibition of Akt activity negative feedback IRS 100 transcription activators FOXOs repressor activity myocardin-related transcription subset genes Akt-mediated downregulation protein degradation hypertrophy proteolysis cardiac function cardiac remodeling ubiquitin proteasome degradation pathway pressure-induced hypertrophy myocardium chemically-mediated inhibition of 26S pressure overload hypertrophy phosphorylation eIF2-alpha downregulation global protein 26S proteasome aberrant proteins myocytes proteasome activation mechanism cardiac atrophy Angiogenesis Cardiac remodeling alterations myocytes extracellular matrix remodeling capillary density spatial rearrangement balance myocardial oxygen processes pathological hypertrophy blood vessels heart thickened heart muscle blood flow myocardium development heart attacks inhibition of vascular endotelial growth factor VEGF pressure overload resulted cardiac hypertrophy promoted progression heart failure TG mice inducible overexpression VEGF abnormal vasculature disruptive edema activation IGF1PI3KAkt pathway physiological setting mechanism action physiological cardiac hypertrophy pro-angiogenic program Akt induction VEGF angiopoietin-2 Ang-2 expression mTORC1-dependent pressure overload TG mice overexpressing active Akt maintained cardiac function VEGF WT longterm Akt activation pathological hypertrophy downregulation mTOR expression VEGF Ang-2 eworthy process of remodelling extracellular matrix proteolytic systems metalloproteinase MMP family upregulation MMPs control mouse models pathways pathological physiological cardiac hypertrophy identified potential targets development of novel therapeutic strategies treatment heart disease IGF1PI3KAkt pathway critical modulating cardiac growth iropicluxotropic function vasculogenesis development physiological hypertrophy mechanisms targets pathway pathways drug discovery selective applications modulating cardiac function Glucose-6-Phosphate Dehydrogenase Nonarteritic Anterior Ischemic Optic Neuropathy Glucose-6-Phosphate Dehydrogenase G6PD deficiency NA-AION human genetic abnormalities prevalence G6PD-deficient protected ischemic heart cerebrovascular disease retinal vein occlusion frequency nonarteritic anterior ischemic optic neuropathy ascertain offer protection Erythrocyte G6PD quantitative assay age- gender-matched comparison Multiple logistic regression models controls Differences cases controls statistically significant P Multiple conditional logistic regression analysis covariates hypertension diabetes hypercholesterolemia significantly associated risk OR CI P adjustment hypertension diabetes hypercholesterolemia association statistically significant adjustment systolic diastolic blood pressure plasma glucose cholesterol levels gender significant G6PD-deficient Glucose-6-Phosphate Dehydrogenase G6PD cytoplasmatic enzyme cells carbon flow pentose phosphate pathway extramitochondrial Nicotine-Adenosine-Dinucleotide Phosphate coenzyme NADPH step glucose-6-phosphate 6-phosphogluconate pentose phosphate pathway erythrocytes defense oxidative G6PD activity NADPH gene encoding G6PD distal long arm X chromosome b Xq28 300 alleles missense point mutation G6PD gene sequence allele associated levels enzyme activity WHO class II prevalence ranges haemolytic anemia deficient phenotype Nonarteritic anterior ischemic optic neuropathy acute optic neuropathy multifactorial disease retinal vein occlusion cardiovascular disease cerebrovascular risk factors systemic hypertension diabetes mellitus sclerosis ischemic heart cerebrovascular occlusion protective effect ischemic disorder optic nerve
case-control design controls Sample size confidence level two-tailed test statistical power odds ratio G6PD prevalence rate case-control ratio
inclusion criterion case group diagnosis optic nerve edema pallor disc edema characteristic retinal nerve fiber layer conventional automated visual field examination ophthalmic evaluation best corrected visual acuity BCVA slit-lamp examination applanation fundus biomicroscopy fluoroscein angiography automated visual field examination Humphrey Field Analyzer test Visual fields types systemic hypertension diabetes mellitus hypercholesterolemia cardio- cerebrovascular status presence of angina myocardial infarction transient ischemic attacks stroke Exclusion criteria neurological systemic ocular disorder optic disc edema visual impairment
Two age- gender-matched controls case selected cataract register Exclusion criteria AION retinal vein occlusion retinal artery occlusion ophthalmic evaluation BCVA slit-lamp examination applanation tonometry fundus examination Medical conditions including systemic hypertension diabetes mellitus hypercholesterolemia cardio- cerebrovascular status presence angina myocardial infarction transient ischemic attacks stroke Controls recruited concurrently recruitment period
Definitions of systemic hypertension diabetes tenets Declaration of Helsinki consent inclusion
Red blood cell G6PD activity quantitative assay G6PD 6PGD Quantitative testing routinely
Categorical values Chi-square test differences cases controls quantitative variables analyzed Student’s t test Multivariate logistic regression models covariates age gender known risk factors systemic hypertension diabetes mellitus hypercholesterolemia significance of association Multivariate analyses adjustment systolic diastolic blood pressure plasma glucose cholesterol levels Odd ratios ORs confidence intervals CIs calculated P values study group consisted mean age ± eye visual acuity intraocular pressure glaucoma eye movements visual loss recovery vision Automated visual field examination altitudinal field eyes cecocentral defect broad arcuate scotomas nasal depression systemic characteristic levels of plasma glucose systemic hypertension diabetes angina myocardial infarction transient ischemic attacks stroke systolic diastolic blood pressure plasma cholesterol significantly higher frequency hypercholesterolemia significantly lower frequency control subjects Enzyme deficiency hemizygotes homozygote drug-induced hemolysis
Multiple logistic regression results multiple conditional analysis systemic hypertension diabetes hypercholesterolemia ORs NA- AION significantly associated risk vascular disorder model hypercholesterolemia hypertension diabetes significantly associated increased risk NA- AION
Even adjustment coning factors hypertension diabetes hypercholesterolemia association statistically significant gender significant association analyses adjusted systolic diastolic blood pressure plasma glucose cholesterol levels Adjustment factors continuous variables produced hypertension diabetes hypercholesterolemia NA- AION categorized gender lack of association NA- AION G6PD-deficient female population significantly risk of less risk non-significant corroborate earlier reports associating hypercholesterolemia
enzyme deficiency humans estimated highly correlated distribution current past malaria endemicity balanced polymorphism resistance infection falciparum malaria
sudden visual loss circulatory insufficiency optic nerve head systemic conditions decrease optic nerve head perfusion microvascular occlusion reduced perfusion pressure marked nocturnal arterial hypotension particularly anomalous optic disc NA- AION mechanical obstruction axoplasmatic flow microvascular compression optic disc edema
arteritic AION giant cell arteritis infiltration short posterior ciliary arteries ischemic necrosis of prelaminar laminar retrolaminar portions optic nerve exact pathophysiology rapid onset stable course poor recovery association vascular risk factors vascular cause pathogenetic impairment optic disc circulation exacerbated structural nerve supporting structures nerve head inadequate oxygenation ischemia axonal swelling microvascular compression ischemia progressive nerve damage Nocturnal systemic hypotension ischemia case-control study significantly higher levels plasma cholesterol significantly higher frequency of hypercholesterolemia multiple conditional analysis hypercholesterolemia significantly associated increased risk consistent earlier studies suggesting hypercholesterolemia well-known risk factor coronary heart disease Hypercholesterolemia damage small blood vessels impairing endolial vasodilator function interfering nitric oxide NO potent vasodilator antiarogenic effects
levels of systolic diastolic blood pressure than control subjects rates systemic hypertension multiple conditional analysis association systemic hypertension result in agreement
Multiple conditional logistic regression analysis revealed significantly associated risk adjustment systemic hypertension diabetes hypercholesterolemia association remained statistically significant Similar results obtained adjusting systolic or diastolic blood pressure plasma glucose cholesterol levels thus demonstrating association is indeed robust gender lack of association protective effect retinal vein occlusion G6PD-deficient susceptible ocular vascular disorders
heterozygous protection retinal vein occlusion hemizygous G6PD-deficient erytrocytes X chromosome hemizygous deficient erythrocytes
risk factors vascular disease control group cataract surgery selection bias frequency susceptibility cataract genetically homogeneous
cholesterol cell growth has plasma intracellular cholesterol metabolism esterification G6PD-deficient esterify cholesterol arteries progression sclerotic process posterior ciliary arteries normal autoregulatory mechanisms optic nerve head vasculature prelaminar region risk levels NO glutathione physiological scavenger NO factor occurrence vascular diseases G6PD- deficient NO S-nitrosocysteine vasodilators scavenger of superoxide radicals toxicity preventing oxidation of low-density lipoproteins platelet aggregation leukocyte adhesion vascular smooth muscle proliferation ionplatelet aggregation release platelet serotonin ischemic optic nerve damage vasoconstriction impairment autoregulation vascular disorders G6PD-