285
Views
0
CrossRef citations to date
0
Altmetric
Review

Placenta Growth Factor and Sflt-1 As Biomarkers in Ischemic Heart Disease and Heart Failure: A Review

, &
Pages 785-799 | Received 28 Dec 2018, Accepted 08 May 2019, Published online: 03 Jun 2019

References

  • Benjamin EJ , ViraniSS, CallawayCWet al. Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation137(12), e67–e492 (2018).
  • Van Berlo JH , MolkentinJD. An emerging consensus on cardiac regeneration. Nat. Med.20(12), 1386–1393 (2014).
  • Cai CL , MolkentinJD. The elusive progenitor cell in cardiac regeneration: slip slidin’ away. Circ. Res.120(2), 400–406 (2017).
  • Morrow DA , d e LemosJA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation115(8), 949–952 (2007).
  • Hlatky MA , GreenlandP, ArnettDKet al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation119(17), 2408–2416 (2009).
  • McCarthy CP , McEvoyJW, JanuzziJL Jr. Biomarkers in stable coronary artery disease. Am. Heart J.196, 82–96 (2018).
  • Ibrahim NE , GagginHK, KonstamMA, JanuzziJL Jr. Established and emerging roles of biomarkers in heart failure clinical trials. Circ. Heart Fail9(9), pii:e002528 (2016).
  • Dewerchin M , CarmelietP. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb. Perspect. Med.2(8), pii:a011056 (2012).
  • Maglione D , GuerrieroV, VigliettoG, Delli-BoviP, PersicoMG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl Acad. Sci. USA88(20), 9267–9271 (1991).
  • Persico MG , VincentiV, DipalmaT. Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr. Top. Microbiol. Immunol.237, 31–40 (1999).
  • De Falco S . The discovery of placenta growth factor and its biological activity. Exp. Mol. Med.44(1), 1–9 (2012).
  • Failla CM , CarboM, MoreaV. Positive and negative regulation of angiogenesis by soluble vascular endothelial growth factor receptor-1. Int. J. Mol. Sci.19(5), pii:E1306 (2018).
  • Autiero M , WaltenbergerJ, CommuniDet al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat. Med.9(7), 936–943 (2003).
  • Kendall RL , ThomasKA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl Acad. Sci. USA90(22), 10705–10709 (1993).
  • Kendall RL , WangG, ThomasKA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem. Biophys. Res. Commun.226(2), 324–328 (1996).
  • Tidwell SC , HoHN, ChiuWH, TorryRJ, TorryDS. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am. J. Obstet. Gynecol.184(6), 1267–1272 (2001).
  • Torry DS , WangHS, WangTH, CaudleMR, TorryRJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am. J. Obstet. Gynecol.179(6), 1539–1544 (1998).
  • Wolf M , ShahA, LamCet al. Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies. Am. J. Obstet. Gynecol.193(1), 16–22 (2005).
  • Levine RJ , MaynardSE, QianCet al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med.350(7), 672–683 (2004).
  • Ahmad S , AhmedA. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ. Res.95(9), 884–891 (2004).
  • Caillon H , TardifC, DumontetE, WinerN, MassonD. Evaluation of sFlt-1/PlGF ratio for predicting and improving clinical management of pre-eclampsia: experience in a specialized perinatal care center. Ann. Lab. Med.38(2), 95–101 (2018).
  • Chau K , HennessyA, MakrisA. Placental growth factor and pre-eclampsia. J. Hum. Hypertens31(12), 782–786 (2017).
  • Behrens I , BasitS, LykkeJAet al. Hypertensive disorders of pregnancy and peripartum cardiomyopathy: a nationwide cohort study. PLoS ONE14(2), e0211857 (2019).
  • Patten IS , RanaS, ShahulSet al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature485(7398), 333–338 (2012).
  • Llurba E , SanchezO, FerrerQet al. Maternal and foetal angiogenic imbalance in congenital heart defects. Eur. Heart J.35(11), 701–707 (2014).
  • De Falco S , GiganteB, PersicoMG. Structure and function of placental growth factor. Trends Cardiovasc. Med.12(6), 241–246 (2002).
  • Carmeliet P , MoonsL, LuttunAet al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med7(5), 575–583 (2001).
  • Luttun A , TjwaM, CarmelietP. Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann. N. Y. Acad. Sci.979, 80–93 (2002).
  • Oura H , BertonciniJ, VelascoP, BrownLF, CarmelietP, DetmarM. A critical role of placental growth factor in the induction of inflammation and edema formation. Blood101(2), 560–567 (2003).
  • Iwasaki H , KawamotoA, TjwaMet al. PlGF repairs myocardial ischemia through mechanisms of angiogenesis, cardioprotection and recruitment of myo-angiogenic competent marrow progenitors. PLoS ONE6(9), e24872 (2011).
  • Gigante B , TarsitanoM, CiminiV, DeFalco S, PersicoMG. Placenta growth factor is not required for exercise-induced angiogenesis. Angiogenesis7(3), 277–284 (2004).
  • Accornero F , MolkentinJD. Placental growth factor as a protective paracrine effector in the heart. Trends Cardiovasc Med21(8), 220–224 (2011).
  • Accornero F , Van BerloJH, BenardMJ, LorenzJN, CarmelietP, MolkentinJD. Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism. Circ Res109(3), 272–280 (2011).
  • Wu M , PokreiszP, SwinnenMet al. Sustained placental growth factor-2 treatment does not aggravate advanced atherosclerosis in ischemic cardiomyopathy. J. Cardiovasc. Transl. Res.10(4), 348–358 (2017).
  • Khurana R , MoonsL, ShafiSet al. Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation. Circulation111(21), 2828–2836 (2005).
  • Roncal C , BuysschaertI, GerdesNet al. Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable lesions. Cardiovasc. Res.86(1), 29–36 (2010).
  • McGraw AP , BagleyJ, ChenWSet al. Aldosterone increases early atherosclerosis and promotes plaque inflammation through a placental growth factor-dependent mechanism. J. Am. Heart Assoc.2(1), e000018 (2013).
  • Torry RJ , TomanekRJ, ZhengW, MillerSJ, LabarrereCA, TorryDS. Hypoxia increases placenta growth factor expression in human myocardium and cultured neonatal rat cardiomyocytes. J. Heart Lung Transplant.28(2), 183–190 (2009).
  • Sands M , HowellK, CostelloCM, McLoughlinP. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung. Respir. Res.12, 17 (2011).
  • Kelly BD , HackettSF, HirotaKet al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ. Res.93(11), 1074–1081 (2003).
  • Yonekura H , SakuraiS, LiuXet al. Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis. J. Biol. Chem.274(49), 35172–35178 (1999).
  • Loboda A , JazwaA, JozkowiczA, MolemaG, DulakJ. Angiogenic transcriptome of human microvascular endothelial cells: effect of hypoxia, modulation by atorvastatin. Vascul. Pharmacol.44(4), 206–214 (2006).
  • Torry DS , HinrichsM, TorryRJ. Determinants of placental vascularity. Am. J. Reprod. Immunol.51(4), 257–268 (2004).
  • Gleadle JM , EbertBL, FirthJD, RatcliffePJ. Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am. J. Physiol.268(6 Pt 1), C1362–1368 (1995).
  • Luttun A , TjwaM, MoonsLet al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med.8(8), 831–840 (2002).
  • Takeda Y , UemuraS, IwamaHet al. Treatment with recombinant placental growth factor (PlGF) enhances both angiogenesis and arteriogenesis and improves survival after myocardial infarction. Circ. J.73(9), 1674–1682 (2009).
  • Liu X , ClausP, WuMet al. Placental growth factor increases regional myocardial blood flow and contractile function in chronic myocardial ischemia. Am. J. Physiol. Heart Circ. Physiol.304(6), H885–894 (2013).
  • Wu M , ClausP, Vanden DriesscheNet al. Placental growth factor 2 – a potential therapeutic strategy for chronic myocardial ischemia. Int. J. Cardiol.203, 534–542 (2016).
  • Kolakowski S Jr , BerryMF, AtluriPet al. Placental growth factor provides a novel local angiogenic therapy for ischemic cardiomyopathy. J. Card. Surg.21(6), 559–564 (2006).
  • Binsalamah ZM , PaulA, KhanAA, PrakashS, Shum-TimD. Intramyocardial sustained delivery of placental growth factor using nanoparticles as a vehicle for delivery in the rat infarct model. Int. J. Nanomedicine6, 2667–2678 (2011).
  • Luo L , ChenB, HuangYet al. Cardioprotective activity of placental growth factor combined with oral supplementation of L-arginine in a rat model of acute myocardial infarction. Drug Design Dev. Ther.10, 3483–3492 (2016).
  • Roncal C , BuysschaertI, ChorianopoulosEet al. Beneficial effects of prolonged systemic administration of PlGF on late outcome of post-ischaemic myocardial performance. J. Pathol.216(2), 236–244 (2008).
  • Bearzi C , GargioliC, BaciDet al. PlGF-MMP9-engineered iPS cells supported on a PEG-fibrinogen hydrogel scaffold possess an enhanced capacity to repair damaged myocardium. Cell Death Dis.5(1), e1053 (2014).
  • Moriya J . Critical roles of inflammation in atherosclerosis. J. Cardiol.73(1), 22–27 (2018).
  • Pilarczyk K , SattlerKJ, GaliliOet al. Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization. Atherosclerosis196(1), 333–340 (2008).
  • Kim SY , LeeSH, ParkSet al. Vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, and the severity of coronary artery disease. Angiology62(2), 176–183 (2011).
  • Chung NA , LydakisC, BelgoreF, Li-Saw-HeeFL, BlannAD, LipGY. Angiogenesis, thrombogenesis, endothelial dysfunction and angiographic severity of coronary artery disease. Heart89(12), 1411–1415 (2003).
  • Onoue K , UemuraS, TakedaYet al. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Circulation120(24), 2470–2477 (2009).
  • Hamsten A , WalldiusG, SzamosiA, DahlenG, DeFaire U. Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction. Circulation73(6), 1097–1110 (1986).
  • Kodama Y , KittaY, NakamuraTet al. Atorvastatin increases plasma soluble fms-like tyrosine kinase-1 and decreases vascular endothelial growth factor and placental growth factor in association with improvement of ventricular function in acute myocardial infarction. J. Am. Coll. Cardiol.48(1), 43–50 (2006).
  • Kapur NK , HeffernanKS, YunisAAet al. Elevated soluble fms-like tyrosine kinase-1 levels in acute coronary occlusion. Arterioscler. Thromb. Vasc. Biol.31(2), 443–450 (2011).
  • Fong SW , FewLL, SeeToo WCet al. Systemic and coronary levels of CRP, MPO, sCD40L and PlGF in patients with coronary artery disease. BMC Res. Notes8, 679 (2015).
  • Apple FS , PearceLA, ChungA, LerR, MurakamiMM. Multiple biomarker use for detection of adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. Clin. Chem.53(5), 874–881 (2007).
  • Zhang M , LuS, WuXet al. Multimarker approach for the prediction of cardiovascular events in patients with mild to moderate coronary artery lesions. A 3-year follow-up study. Int. Heart J.53(2), 85–90 (2012).
  • Lenderink T , HeeschenC, FichtlschererSet al. Elevated placental growth factor levels are associated with adverse outcomes at four-year follow-up in patients with acute coronary syndromes. J. Am. Coll. Cardiol.47(2), 307–311 (2006).
  • Cassidy A , ChiuveSE, MansonJE, RexrodeKM, GirmanCJ, RimmEB. Potential role for plasma placental growth factor in predicting coronary heart disease risk in women. Arterioscler. Thromb. Vasc. Biol.29(1), 134–139 (2009).
  • Markovic M , IgnjatovicS, DajakM, Majkic-SinghN. Utility of placental growth factor for prediction of 30-day adverse event in emergency department population with non-ST elevation acute coronary syndrome. Clin. Lab.56(5-6), 215–222 (2010).
  • Bui AH , BonacaMP, SabatineMSet al. Elevated concentration of placental growth factor (PlGF) and long term risk in patients with acute coronary syndrome in the PROVE IT-TIMI 22 trial. J. Thrombosis Thrombolysis34(2), 222–228 (2012).
  • Iwama H , UemuraS, NayaNet al. Cardiac expression of placental growth factor predicts the improvement of chronic phase left ventricular function in patients with acute myocardial infarction. J. Am. Coll. Cardiol.47(8), 1559–1567 (2006).
  • Onoue K , UemuraS, TakedaYet al. Usefulness of soluble fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction. Am. J. Cardiol.104(11), 1478–1483 (2009).
  • Hochholzer W , ReichlinT, StelzigCet al. Impact of soluble fms-like tyrosine kinase-1 and placental growth factor serum levels for risk stratification and early diagnosis in patients with suspected acute myocardial infarction. Eur. Heart J.32(3), 326–335 (2011).
  • Kameda R , Yamaoka-TojoM, MakinoAet al. Soluble fms-like tyrosine kinase 1 is a novel predictor of brain natriuretic peptide elevation. Int. Heart J.54(3), 133–139 (2013).
  • Matsumoto T , UemuraS, TakedaYet al. An elevated ratio of placental growth factor to soluble fms-like tyrosine kinase-1 predicts adverse outcomes in patients with stable coronary artery disease. Intern. Med.52(10), 1019–1027 (2013).
  • Sinning C , SchnabelRB, ZellerTet al. Prognostic use of soluble fms-like tyrosine kinase-1 and placental growth factor in patients with coronary artery disease. Biomark. Med.10(1), 95–106 (2016).
  • Sun Z , ShenY, LuLet al. Increased serum level of soluble vascular endothelial growth factor receptor-1 is associated with poor coronary collateralization in patients with stable coronary artery disease. Circ. J.78(5), 1191–1196 (2014).
  • Matsui M , UemuraS, TakedaYet al. Placental growth factor as a predictor of cardiovascular events in patients with CKD from the NARA-CKD study. J. Am. Soc. Nephrol.26(11), 2871–2881 (2015).
  • Zheng SL , ChanFT, NabeebaccusAAet al. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart104(5), 407–415 (2018).
  • De Boer RA , NayorM, DefilippiCRet al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol.3(3), 215–224 (2018).
  • Chow SL , MaiselAS, AnandIet al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation135(22), e1054–e1091 (2017).
  • Heil B , TangWH. Biomarkers: their potential in the diagnosis and treatment of heart failure. Cleve Clin. J. Med.82(12 Suppl. 2), S28–S35 (2015).
  • Liquori ME , ChristensonRH, CollinsonPO, DefilippiCR. Cardiac biomarkers in heart failure. Clin. Biochem.47(6), 327–337 (2014).
  • Cohen-Solal A , LaribiS, IshiharaSet al. Prognostic markers of acute decompensated heart failure: the emerging roles of cardiac biomarkers and prognostic scores. Arch. Cardiovasc. Dis.108(1), 64–74 (2015).
  • Jungbauer CG , RiedlingerJ, BlockDet al. Panel of emerging cardiac biomarkers contributes for prognosis rather than diagnosis in chronic heart failure. Biomark. Med.8(6), 777–789 (2014).
  • Shirazi LF , BissettJ, RomeoF, MehtaJL. Role of inflammation in heart failure. Curr. Atheroscler. Rep.19(6), 27 (2017).
  • Paulus WJ , TschopeC. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. College Cardiol.62(4), 263–271 (2013).
  • Hartupee J , MannDL. Positioning of inflammatory biomarkers in the heart failure landscape. J. Cardiovasc. Transl. Res.6(4), 485–492 (2013).
  • Ueland T , GullestadL, NymoSH, YndestadA, AukrustP, AskevoldET. Inflammatory cytokines as biomarkers in heart failure. Clin. Chim. Acta443, 71–77 (2015).
  • Nakamura T , FunayamaH, KuboNet al. Elevation of plasma placental growth factor in the patients with ischemic cardiomyopathy. Int. J. Cardiol.131(2), 186–191 (2009).
  • Hammadah M , GeorgiopoulouVV, KalogeropoulosAPet al. Elevated soluble fms-like tyrosine kinase-1 and placental-like growth factor levels are associated with development and mortality risk in heart failure. Circ. Heart Fail.9(1), e002115 (2016).
  • Ky B , FrenchB, RuparelKet al. The vascular marker soluble fms-like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure. J. Am. Coll. Cardiol.58(4), 386–394 (2011).
  • Gruson D , HermansMP, FerracinB, AhnSA, RousseauMF. Sflt-1 in heart failure: relation with disease severity and biomarkers. Scand. J. Clin. Lab. Invest.76(5), 411–416 (2016).
  • Gmeiner M , ZimpferD, HolfeldJet al. Improvement of cardiac function in the failing rat heart after transfer of skeletal myoblasts engineered to overexpress placental growth factor. J. Thorac. Cardiovasc. Surg.141(5), 1238–1245 (2011).
  • Zimna A , WiernickiB, KolanowskiTet al. Biological and pro-angiogenic properties of genetically modified human primary myoblasts overexpressing placental growth factor in in vitro and in vivo studies. Arch. Immunol. Ther. Exp. (Warsz.)66(2), 145–159 (2018).
  • Kaza E , AblasserK, PoutiasDet al. Up-regulation of soluble vascular endothelial growth factor receptor-1 prevents angiogenesis in hypertrophied myocardium. Cardiovasc. Res.89(2), 410–418 (2011).
  • Seno A , TakedaY, MatsuiMet al. Suppressed production of soluble fms-like tyrosine kinase-1 contributes to myocardial remodeling and heart failure. Hypertension68(3), 678–687 (2016).
  • Foglia MJ , PossKD. Building and re-building the heart by cardiomyocyte proliferation. Development143(5), 729–740 (2016).
  • Karra R , PossKD. Redirecting cardiac growth mechanisms for therapeutic regeneration. J. Clin. Invest.127(2), 427–436 (2017).
  • Senyo SE , LeeRT, KuhnB. Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res.13(3), 532–541 (2014).
  • Uygur A , LeeRT. Mechanisms of cardiac regeneration. Dev. Cell.36(4), 362–374 (2016).
  • Kamo T , AkazawaH, KomuroI. Cardiac nonmyocytes in the hub of cardiac hypertrophy. Circulation Research117(1), 89–98 (2015).
  • Segers VFM , BrutsaertDL, DeKeulenaer GW. Cardiac remodeling: endothelial cells have more to say than just NO. Front. Physiol.9, 382 (2018).
  • Jaba IM , ZhuangZW, LiNet al. NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth. J. Clin. Invest.123(4), 1718–1731 (2013).
  • Yang F , JinC, JiangYJ, LiJ, DiY, FuDL. Potential role of soluble VEGFR-1 in antiangiogenesis therapy for cancer. Expert. Rev. Anticancer Ther.11(4), 541–549 (2011).
  • Di Marco GS , KentrupD, ReuterSet al. Soluble Flt-1 links microvascular disease with heart failure in CKD. Basic Res. Cardiol.110(3), 30 (2015).
  • Maynard SE , MinJY, MerchanJet al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest.111(5), 649–658 (2003).
  • Ohanyan V , SisakianH, PeketiP, ParikhA, ChilianW. A chicken and egg conundrum: coronary microvascular dysfunction and heart failure with preserved ejection fraction. Am. J. Physiol. Heart Circ. Physiol.314(6), H1262–H1263 (2018).
  • Shah SJ , KitzmanDW, BorlaugBAet al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation134(1), 73–90 (2016).
  • Franssen C , ChenS, UngerAet al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail.4(4), 312–324 (2016).
  • Dryer K , GajjarM, NarangNet al. Coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. Am. J. Physiol. Heart Circ. Physiol.314(5), H1033–H1042 (2018).
  • Searle J , MockelM, GwoscSet al. Heparin strongly induces soluble fms-like tyrosine kinase 1 release in vivo and in vitro – brief report. Arterioscler. Thromb. Vasc. Biol.31(12), 2972–2974 (2011).
  • Lavainne F , MeffrayE, PepperRJet al. Heparin use during dialysis sessions induces an increase in the antiangiogenic factor soluble Flt1. Nephrol. Dial. Transplant.29(6), 1225–1231 (2014).
  • Kylhammar D , HesselstrandR, NielsenS, ScheeleC, RadegranG. Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension. Scand. J. Rheumatol.47(4), 319–324 (2018).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.