Primary Prevention of Cardiovascular Disease in Women
References
- Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021 Feb 23;143(8):e254-e743. doi: 10.1161/CIR.0000000000000950
- Saeed A, Kampangkaew J, Nambi V. Prevention of Cardiovascular Disease in Women. Methodist Debakey Cardiovasc J. 2017 Oct-Dec;13:185-192. doi: 10.14797/mdcj-13-4-185
- Gulati M, Shaw LJ, Bairey Merz CN. Myocardial ischemia in women: lessons from the NHLBI WISE study. Clin Cardiol. 2012 Mar;35(3):141-8. doi: 10.1002/clc.21966
- Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation. 2011 Sep 27;124(13):1414-25. doi: 10.1161/CIRCULATIONAHA.111.026542
- Diabetesatlas.org [Internet]. The Netherlands: International Diabetes Federation; c2024. IDF Diabetes Atlas; 2024 [cited 2024 Feb 2]. Available from:
https://diabetesatlas.org/ - Elder P, Sharma G, Gulati M, Michos ED. Identification of female-specific risk enhancers throughout the lifespan of women to improve cardiovascular disease prevention. Am J Prev Cardiol. 2020 Jun 6;2:100028. doi: 10.1016/j.ajpc.2020.100028
- Khan SU, Khan MZ, Subramanian CR, et al. Participation of women and older participants in randomized clinical trials of lipid-lowering therapies: a systematic review. JAMA Netw Open. 2020 May 1;3(5):
e205202 . doi: 10.1001/jamanetworkopen.2020.5202 - Osibogun O, Ogunmoroti O, Michos ED. Polycystic ovary syndrome and cardiometabolic risk: Opportunities for cardiovascular disease prevention. Trends Cardiovasc Med. 2020 Oct;30(7):399-404. doi: 10.1016/j.tcm.2019.08.010
- Oliver-Williams C, Vassard D, Pinborg A, Schmidt L. Risk of cardiovascular disease for women with polycystic ovary syndrome: results from a national Danish registry cohort study. Eur J Prev Cardiol. 2020 Oct 13;28(12):e39-e41. doi: 10.1177/2047487320939674
- Berni TR, Morgan CL, Rees DA. Women With Polycystic Ovary Syndrome Have an Increased Risk of Major Cardiovascular Events: a Population Study. J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3369-e3380. doi: 10.1210/clinem/dgab392
- Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018 Sep 1;33(9):1602-1618. doi: 10.1093/humrep/dey256
- Kavanaugh ML, Pliskin E. Use of contraception among reproductive-aged women in the United States, 2014 and 2016. F S Rep. 2020 Jul 9;1(2):83-93. doi: 10.1016/j.xfre.2020.06.006
- Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012 Jun 14;366(24):2257-66. doi: 10.1056/NEJMoa1111840
- Teal S, Edelman A. Contraception Selection, Effectiveness, and Adverse Effects: A Review. JAMA. 2021 Dec 28;326(24):2507-2518. doi: 10.1001/jama.2021.21392
- Roach RE, Helmerhorst FM, Lijfering WM, Stijnen T, Algra A, Dekkers OM. Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev. 2015 Aug 27;2015(8):CD011054. doi: 10.1002/14651858.CD011054.pub2
- Martin AS, Monsour M, Kissin DM, Jamieson DJ, Callaghan WM, Boulet SL. Trends in Severe Maternal Morbidity After Assisted Reproductive Technology in the United States, 2008-2012. Obstet Gynecol. 2016 Jan;127(1):59-66. doi: 10.1097/AOG.0000000000001197
- Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, Ekbom A. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. BMJ. 2013 Jan 15;346:
e8632 . doi: 10.1136/bmj.e8632 - Westerlund E, Brandt L, Hovatta O, Wallén H, Ekbom, Henriksson P. Incidence of hypertension, stroke, coronary heart disease, and diabetes in women who have delivered after in vitro fertilization: a population-based cohort study from Sweden. Fertil Steril. 2014 Oct;102(4):1096-102. doi: 10.1016/j.fertnstert.2014.06.024
- Udell JA, Lu H, Redelmeier DA. Failure of fertility therapy and subsequent adverse cardiovascular events. CMAJ. 2017 Mar 13;189(10):E391-E397. doi: 10.1503/cmaj.160744
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10;140(11):e596-e646. doi: 10.1161/CIR.0000000000000678
- Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007 Nov 10;335(7627):974. doi: 10.1136/bmj.39335.385301.BE
- Ferranti EP, Jones EJ, Hernandez TL. Pregnancy Reveals Evolving Risk for Cardiometabolic Disease in Women. J Obstet Gynecol Neonatal Nurs. 2016 May-Jun;45(3):413-25. doi: 10.1016/j.jogn.2016.02.004
- Garovic VD, Bailey KR, Boerwinkle E, et al. Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J Hypertens. 2010 Apr;28(4):826-33. doi: 10.1097/HJH.0b013e328335c29a
- Garovic VD, White WM, Vaughan L, et al Incidence and Long-Term Outcomes of Hypertensive Disorders of Pregnancy. J Am Coll Cardiol. 2020 May 12;75(18):2323-2334. doi: 10.1016/j.jacc.2020.03.028
- Haug EB, Horn J, Markovitz A, et al. Life course trajectories of cardiovascular risk factors in women with and without hypertensive disorders in first pregnancy: the HUNT study in Norway. J Am Heart Assoc. 2018 Aug 7;7(15):
e009250 . doi: 10.1161/JAHA.118.009250 - American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 203: Chronic Hypertension in Pregnancy. Obstet Gynecol. 2019 Jan;133(1):e26-e50. doi: 10.1097/AOG.0000000000003020
- Garovic VD, Dechend R, Easterling T, et al. Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association. Hypertension. 2022 Feb;79(2):e21-e41. doi: 10.1161/HYP.0000000000000208
- Wu P, Haththotuwa R, Kwok CS, et al. Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2017 Feb;10(2):
e003497 . doi: 10.1161/CIRCOUTCOMES.116.003497 - Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005 Nov 19;366(9499):1797-803. doi: 10.1016/S0140-6736(05)67726-4
- Bateman BT, Bansil P, Hernandez-Diaz S, Mhyre JM, Callaghan WM, Kuklina EV. Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admissions. Am J Obstet Gynecol. 2012 Feb;206(2):134.e1-8. doi: 10.1016/j.ajog.2011.10.878
- Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88
- Magro-Malosso ER, Saccone G, Di Tommaso M, Roman A, Berghella V. Exercise during pregnancy and risk of gestational hypertensive disorders: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017 Aug;96(8):921-931. doi: 10.1111/aogs.13151
- Mottola MF, Davenport MH, Ruchat SM, et al. No. 367-2019 Canadian Guideline for Physical Activity throughout Pregnancy. J Obstet Gynaecol Can. 2018 Nov;40(11):1528-1537. doi: 10.1016/j.jogc.2018.07.001
- ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol. 2018 Jul;132(1):e44-e52. doi: 10.1097/AOG.0000000000002708
- Rosano G, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: the evidence. Climacteric. 2007 Feb;10 Suppl 1:19-24. doi: 10.1080/13697130601114917
- Kim JK, Pedram A, Razandi M, Levin ER. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem. 2006 Mar 10;281(10):6760-7. doi: 10.1074/jbc.M511024200
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women›s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. doi: 10.1001/jama.288.3.321
- Gregersen I, Høibraaten E, Holven KB, et al. Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women. Thrombosis Res. 2019 Dec;184:1-7. doi: 10.1016/j.thromres.2019.10.005
- Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015 Mar 10;2015(3):Cd002229. doi: 10.1002/14651858.CD002229.pub4
- US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement. JAMA. 2017 Dec 12;318(22):2224-2233. doi: 10.1001/jama.2017.18261
- Lundberg GP, Wenger NK. Menopause Hormone Therapy: What a Cardiologist Needs to Know. Am Coll Cardiol. 2019 Jul 18;2023.
- Cancer.org [Internet]. Atlanta, GA: American Cancer Society; c2024. Cokkinides V, Albano J, Samuels A, Ward M, Thum J.
Cancer Facts & Figures 2005 ; 2005 {cited 2024 Feb 2]. Available from:.file:///C:/Users/18059/Downloads/cancer-facts-and-figures-2005.pdf - Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 Nov;91(5):710-7. doi: 10.7326/0003-4819-91-5-710
- Narayan HK, Finkelman B, French B, et al. Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 years of Follow-Up. Circulation. 2017 Apr 11;135(15):1397-1412. doi: 10.1161/CIRCULATIONAHA.116.023463
- Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA Cancer J Clin. 2016 Jul;66(4):309-25. doi: 10.3322/caac.21341
- Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol. 1996 Aug;27(8):766-73. doi: 10.1016/s0046-8177(96)90447-5
- Bradshaw PT, Stevens J, Khankari N, Teitelbaum SL, Neugut AI, Gammon MD. Cardiovascular Disease Mortality Among Breast Cancer Survivors. Epidemiology. 2016 Jan;27(1):6-13. doi: 10.1097/EDE.0000000000000394
- Shahid I, Yamani N, Ali A, et al. Meta-analysis Evaluating the Use of Statins to attenuate Cardiotoxicity in Cancer Patients receiving Anthracyclines and Trastuzumab-based Chemotherapy. Am J Cardiol. 2021 Oct 1;156:142-145. doi: 10.1016/j.amjcard.2021.07.001
- Mir A, Badi Y, Bugazia S, et al. Efficacy and safety of cardioprotective drugs in chemotherapy-induced cardiotoxicity: an updated systematic review & network meta-analysis. Cardiooncology. 2023;9:10. doi: 10.1186/s40959-023-00159-0
- Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018 Jul 1;39(25):2401-2408. doi: 10.1093/eurheartj/ehy217
- Michos ED, Blaha MJ, Blumenthal RS. Use of the coronary artery calcium score in discussion of initiation of statin therapy in primary prevention. Mayo Clin Proc. 2017 Dec;92(12):1831-1841. doi: 10.1016/j.mayocp.2017.10.001
- Fulcher J, O’Connell R, Voysey M, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015 Apr 11;385(9976):1397-405. doi: 10.1016/S0140-6736(14)61368-4
- Cho L, Davis M, Elgendy I, et al. Summary of Updated Recommendations for Primary Prevention of Cardiovascular Disease in Women. J Am Coll Cardiol. 2020 May 26;75(20):2602-2618. doi: 10.1016/j.jacc.2020.03.060
- Nanna MG, Wang TY, Xiang Q, et al. Sex Differences in the Use of Statins in Community Practice. Circ Cardiovasc Qual Outcomes. 2019 Aug;12(8):
e005562 . doi: 10.1161/CIRCOUTCOMES.118.005562 - Peters SAE, Muntner P, Woodward M. Sex Differences in the Prevalence of, and Trends in, Cardiovascular Risk Factors, Treatment, and Control in the United States, 2001 to 2016. Circulation. 2019 Feb 19;139(8):1025-1035. doi: 10.1161/CIRCULATIONAHA.118.035550
- Koopman C, Vaartjes I, Heintjes EM, et al. Persisting gender differences and attenuating age differences in cardiovascular drug use for prevention and treatment of coronary heart disease, 1998-2010. Eur Heart J. 2013 Nov;34(41):3198-205. doi: 10.1093/eurheartj/eht368
- Khan MS, Shahid I, Siddiqi TJ, et al. Ten-year Trends in Enrollment of Women and Minorities in Pivotal Trials Supporting Recent US Food and Drug Administration Approval of Novel Cardiometabolic Drugs. J Am Heart Assoc. 2020 Jun 2;9(11):
e015594 . doi: 10.1161/JAHA.119.015594 - Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015 Feb 18;36(17):1012-22. doi: 10.1093/eurheartj/ehv043
- FDA.gov [Internet]. Silver Spring, MD: US Food & Drug Administration; c2024.
FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins ; 2022 Jan 14 [cited 2024 Feb 5]. Available from:https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy#:~:text=On%20July%2020%2C%202021%2C%20FDA,they%20learn%20they%20are%20pregnant - Costantine MM, West H, Wisner KL, et al. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol. 2021 Dec;225(6):666.e1-666.e15. doi: 10.1016/j.ajog.2021.05.018
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 3;376(18):1713-1722. doi: 10.1056/NEJMoa1615664
- Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379:2097-2107. doi: 10.1056/NEJMoa1801174
- Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. doi: 10.1056/NEJMoa2215024
- Fuchs FD, Whelton PK. High Blood Pressure and Cardiovascular Disease. Hypertension. 2020 Feb;75(2):285-292. doi: 10.1161/HYPERTENSIONAHA.119.14240
- Sabbatini AR, Kararigas G. Estrogen-related mechanisms in sex differences of hypertension and target organ damage. Biol Sex Differ. 2020 Jun 1;11(1):31. doi: 10.1186/s13293-020-00306-7
- Turnbull F, Woodward M, Neal B, et al. Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008 Nov;29(21):2669-80. doi: 10.1093/eurheartj/ehn427
- Nichols H, Cannon CP, Scirica BM, Fisher NDL. A remote hypertension management program clinical algorithm. Clin Cardiol. 2022 Dec;45(12):1147-1162. doi: 10.1002/clc.23919
- Tita AT, Szychowski JM, Boggess K, et al. Treatment for Mild Chronic Hypertension during Pregnancy. N Engl J Med. 2022 May 12;386(19):1781-1792. doi: 10.1056/NEJMoa2201295
- Bowman L, Mafham M, Wallendszus K, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018 Oct 18;379(16):1529-1539. doi: 10.1056/NEJMoa1804988
- Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018 Sep 22;392(10152):1036-1046. doi: 10.1016/S0140-6736(18)31924-X
- McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med. 2018 Oct 18;379(16):1519-1528. doi: 10.1056/NEJMoa1803955
- Health.gov [Internet]. Rockville, MD: U.S. Department of Health and Human Services; c2024.
Physical Activity Guidelines for Americans , 2nd edition; 2018 [cited 2024 Feb 5]. Available from:https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf - Chen TJ, Whitfield GP, Watson KB, et al. Awareness and Knowledge of the Physical Activity Guidelines for Americans, 2nd Edition. J Phys Act Health. 2023 May 12;20(8):742-751. doi: 10.1123/jpah.2022-0478
- CDC.gov [Internet]. Washington DC: Department of Health and Human Services; c2024.
National Center for Health Statistics . Interactive Summary Health Statistics for Adults: Crude percentages of meeting full guidelines for both aerobic and muscle-strengthening activity for adults aged 18 and over, United States; 2018 Aug 27[cited 2024 Feb 5]. Available from:https://www.cdc.gov/nchs/nhis/ADULTS/www/index.htm - Banks AD. Women and heart disease: missed opportunities. J Midwifery Womens Health. 2008 Sep-Oct;53(5):430-9. doi: 10.1016/j.jmwh.2008.04.008
- Martínez-González MA, Sánchez-Tainta A, Corella D, et al. A provegetarian food pattern and reduction in total mortality in the Prevención con Dieta Mediterránea (PREDIMED) study. Am J Clin Nutr. 2014 Jul;100 Suppl 1:320s-8s. doi: 10.3945/ajcn.113.071431
- Walli-Attaei M, Joseph P, Rosengren A, et al. Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. Lancet. 2020 Jul 11;396(10244):97-109. doi: 10.1016/S0140-6736(20)30543-2
- Elzeneini M, George J, Ashraf H, et al. Impact of a preventive cardiology clinic focusing on lifestyle and nutrition counseling: A pilot analysis. AHJ Plus. 2021 Jun;6:100032. doi: 10.1016/j.ahjo.2021.100032
- Marschner S, Mukherjee S, Watts M, et al. Prevention of Cardiovascular Disease in Women With Pregnancy-Related Risk Factors: A Prospective Women’s Heart Clinic Study. J Am Heart Assoc. 2023 Sep 5;12(17):
e030015 . doi: 10.1161/JAHA.123.030015 - Taha MB, Avenatti E, Li DS, et al. A Checklist Approach for Enhanced Outpatient Guideline-Directed Management in the Secondary Prevention of Atherosclerotic Cardiovascular Disease. Methodist Debakey Cardiovasc J. 2021 Sep 24;17(4):79-86. doi: 10.14797/mdcvj.907
- Whelton SP, Nasir K, Blaha MJ, et al. Coronary artery calcium and primary prevention risk assessment: what is the evidence? An updated meta-analysis on patient and physician behavior. Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):601-7. doi: 10.1161/CIRCOUTCOMES.112.965566
- Agarwala A, Michos ED, Samad Z, Ballantyne CM, Virani SS. The Use of Sex-Specific Factors in the Assessment of Women’s Cardiovascular Risk. Circulation. 2020 Feb 18;141(7):592-599. doi: 10.1161/CIRCULATIONAHA.119.043429
- Persell SD, Brown T, Lee JY, et al. Individualized Risk Communication and Outreach for Primary Cardiovascular Disease Prevention in Community Health Centers: Randomized Trial. Circ Cardiovasc Qual Outcomes. 2015 Nov 8;8(6):560-6. doi: 10.1161/CIRCOUTCOMES.115.001723
- Persell SD, Lloyd-Jones DM, Friesema EM, Cooper AJ, Baker DW. Electronic health record-based patient identification and individualized mailed outreach for primary cardiovascular disease prevention: a cluster randomized trial. J Gen Intern Med. 2013 Apr;28(4):554-60. doi: 10.1007/s11606-012-2268-1
- Gleason-Comstock J, Mozeb G, Louis C. Using the cardiovascular risk profile in a community heart health outreach intervention: Implications for primary care. Ann Fam Med. 2022 Apr 1;20(20 Suppl 1):2961. doi: 10.1370/afm.20.s1.2961
DOI: https://doi.org/10.14797/mdcvj.1313 | Journal eISSN: 1947-6108
Language: English
Page range: 94 - 106
Submitted on: Nov 8, 2023
Accepted on: Jan 10, 2024
Published on: Mar 14, 2024
Published by: Houston Methodist DeBakey Heart & Vascular Center
In partnership with: Paradigm Publishing Services
© 2024 Izza Shahid, Eleonora Avenatti, Anoop Titus, Sadeer Al-Kindi, Khurram Nasir, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.