Пробелы в доказательных данных и необходимость дальнейших исследований

 

Если проанализировать доказательные данные, на основе которых создавались рекомендации 2013 г. по АГ, становится очевидным, что несколько терапевтических проблем продолжаются оставаться открытыми и нуждаются в дальнейшем изучении:

1. Нужно ли назначать медикаментозную антигипертензивную терапию всем больным с АГ 1 степени и низким и средним сердечно-сосудистым риском?

2. Нужно ли назначать медикаментозную антигипертензивную терапию больным старческого возраста с уровнем САД от 140 до 160 мм рт.ст.?

3. Нужно ли назначать медикаментозную терапию пациентам с «гипертонией белого халата»? Можно ли дифференцировать пациентов с этим состоянием, нуждающихся и не нуждающихся в лечении?

4. Нужно ли начинать медикаментозную антигипертензивную терапию в диапазоне высокого нормального АД и если да, то каким больным?

5. Каковы оптимальные офисные значения АД (т.е., наиболее безопасные и обеспечивающие наилучшую протекцию), которых нужно достигать на фоне лечения у пациентов с различными демографическими и клиническими характеристиками?

6. Имеют ли подходы к лечению, основанные на контроле внеофисного АД, преимущество (в виде снижения клинической заболеваемости и смертности, применения меньшего числа препаратов, меньшего числа побочных эффектов) перед подходами, основанными на традиционном офисном контроле АД?

7. Каковы оптимальные значения внеофисного (домашнего и амбулаторного) АД, которых нужно достигать на фоне лечения, и должны ли целевые значения у больных АГ высокого риска быть выше или ниже?

8. Может ли учет значений центрального АД улучшить прогнозирование сердечно-сосудистых событий у нелеченых и леченых больных АГ?

9. Имеют ли инвазивные процедуры для лечения резистентной АГ преимущества перед наилучшей медикаментозной терапией и обеспечивают ли они длительный контроль АД и снижение заболеваемости и смертности?

10. Является ли динамика бессимптомного поражения органов-мишеней, обусловленная лечением, предиктором исходов? Какие параметры или какая комбинация параметров наиболее ценны?

11. Могут ли изменения образа жизни, которые снижают АД, уменьшить также число осложнений и смертность у больных АГ?

12. Способствует ли уменьшение суточной вариабельности АД на фоне лечения лучшему протективному действию антигипертензивной терапии на сердечно-сосудистую систему?

13. Может ли снижение АД существенно уменьшить сердечно-сосудистый риск при резистентной АГ?

Хотя «золотым стандартом» разрешения терапевтических проблем остаются РКИ, точно также ясно, что было бы неразумно ожидать, что на все эти вопросы можно в предвидимом будущем действительно получить ответ с помощью РКИ. Решение некоторых из этих вопросов, например, об уменьшении сердечно-сосудистой заболеваемости и смертности при лечении больных АГ 1 степени с низким риском сердечно-сосудистых заболеваний или о снижении числа сердечно-сосудистых событий при изменении образа жизни, потребовало бы исследований на многих тысячах пациентов в течение очень длительного времени; кроме того, такие исследования вызвали бы ряд этических проблем. Другие вопросы, такие как польза лекарственной терапии при «гипертонии белого халата» или дополнительная прогностическая сила центрального АД, по сравнению с периферическим, могут потребовать больших усилий от исследований при скромной ожидаемой пользе. Представляется целесообразным, по крайней мере, в ближайшие годы, фокусировать РКИ на важных и легче решаемых вопросах, таких как оптимальные целевые значения АД на фоне лечения; значения АД, при которых нужно назначать терапию и целевые значения у больных АГ пожилого и старческого возраста; снижение заболеваемости и смертности при использовании новых подходов к лечению резистентной АГ и возможная польза от лечения пациентов из группы высокого риска, но с высоким нормальным АД. К решению других важных вопросов, например, о прогностическом значении внеофисного АД и поражения органов-мишеней, более реально можно подойти, если добавить оценку этих показателей в дизайн некоторых РКИ, которые планируются в ближайшем будущем.


Литература

1. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21:1011–1053.

2. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105–1187.

3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual datafor one million adults in 61 prospective studies. Lancet 2002; 360:1903–1913.

4. Britton KA, Gaziano JM, Djousse L. Normal systolic blood pressure and risk of heart failure in US male physicians. Eur J Heart Fail 2009; 11:1129–1134.

5. Kalaitzidis RG, Bakris GL. Prehypertension: is it relevant for nephrologists? Kidney Int 2010; 77:194–200.

6. Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the Asia Pacific region. J Hypertens 2003; 21:707–716.

7. Brown DW, Giles WH, Greenlund KJ. Blood pressure parameters and risk of fatal stroke, NHANES II mortality study. Am J Hypertens 2007; 20:338–341.

8. Franklin SS, Gustin WIV, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Haemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 1997; 96:308–315.

9. Vishram JK, Borglykke A, Andreasen AH, Jeppesen J, Ibsen H, J0rgensen T, et al., on behalf of the MORGAM Project. Impact of Age on the Importance of Systolic and Diastolic Blood Pressures for Stroke Risk: The MOnica, Risk, Genetics, Archiving and Monograph (MORGAM) Project. Hypertension 2012; 60:1117–1123.

10. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetieere P, Guize L. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension 1997; 30:1410–1415.

11. Kannel WB, Wolf PA, McGee DL, Dawber TR, McNamara P, Castelli WP. Systolic blood pressure arterial rigidity risk of stroke. The Framingham study. JAMA 1981; 245:1225–1229.

12. Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens 2000; 13:3S–10S.

13. Thomas F, Rudnichi A, Bacri AM, Bean K, Guize L, Benetos A. Cardiovascular mortality in hypertensive men according to presence of associated risk factors. Hypertension 2001; 37:1256–1261.

14. Pickering G. Hypertension. Definitions, natural histories and consequences. Am J Med 1972; 52:570–583.

15. Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens 2009; 27:1719–1742.

16. Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens 2009; 27:963–975.

17. Danon-Hersch N, Marques-Vidal P, Bovet P, Chiolero A, Paccaud F, Pecoud A, et al. Prevalence, awareness, treatment and control of high blood pressure in a Swiss city general population: the Co Laus study. Eur J Cardiovasc Prev Rehabil 2009; 16:66–72.

18. Altun B, Arici M, Nergizoglu G, Derici U, Karatan O, Turgan C, et al. Prevalence, awareness, treatment and control of hypertension in Turkey (the PatenT study) in 2003. J Hypertens 2005; 23:1817–1823.

19. Tugay Aytekin N, Pala K, Irgil E, Akis N, Aytekin H. Distribution of blood pressures in Gemlik District, north-west Turkey. Health Soc Care Community 2002; 10:394–401.

20. Efstratopoulos AD, Voyaki SM, Baltas AA, Vratsistas FA, Kirlas DE, Kontoyannis JT, et al. Prevalence, awareness, treatment and control of hypertension in Hellas, Greece: the Hypertension Study in General Practice in Hellas (HYPERTENSHELL) national study. Am J Hypertens 2006; 19:53–60.

21. Macedo ME, Lima MJ, Silva AO, Alcantara P, Ramalhinho V, Carmona J. Prevalence, awareness, treatment and control of hypertension in Portugal: the PAP study. J Hypertens 2005; 23:1661–1666.

22. Psaltopoulou T, Orfanos P, Naska A, Lenas D, Trichopoulos D, Trichopoulou A. Prevalence, awareness, treatment and control of hypertension in a general population sample of adults in the Greek EPIC study. Int J Epidemiol 2004; 33:1345–1352.

23. Sarafidis PA, Lasaridis A, Gousopoulos S, Zebekakis P, Nikolaidis P, Tziolas I, Papoulidou F. Prevalence, awareness, treatment and control of hypertension in employees of factories of Northern Greece: the Naoussa study. J Hum Hypertens 2004; 18:623–629.

24. Panagiotakos DB, Pitsavos CH, Chrysohoou C, Skoumas J, Papadimitriou L, Stefanadis C, Toutouzas PK. Status and management of hypertension in Greece: role of the adoption of a Mediterranean diet: the Attica study. J Hypertens 2003; 21:1483–1489.

25. Banegas JR, Graciani A, de la Cruz-Troca JJ, Leon-Munoz LM, Guallar-Castillon P, Coca A, et al. Achievement of cardiometabolic targets in aware hypertensive patients in Spain: a nationwide population-based study. Hypertension 2012; 60:898–905.

26. Primatesta P, Poulter NR. Improvement in hypertension management in England: results from the Health Survey for England 2003. J Hypertens 2006; 24:1187–1192.

27. Meisinger C, Heier M, Volzke H, Lowel H, Mitusch R, Hense HW, Ludemann J. Regional disparities of hypertension prevalence and management within Germany. J Hypertens 2006; 24:293–299.

28. Agyemang C, Ujcic-Voortman J, Uitenbroek D, Foets M, Droomers M. Prevalence and management of hypertension among Turkish, Moroccan and native Dutch ethnic groups in Amsterdam, the Netherlands: The Amsterdam Health Monitor Survey. J Hypertens 2006; 24:2169–2176.

29. Agyemang C, Bindraban N, Mairuhu G, Montfrans G, Koopmans R, Stronks K. Prevalence, awareness, treatment and controlofhypertension among Black Surinamese, South Asian Surinamese and White Dutch in Amsterdam, The Netherlands: the SUNSET study. J Hypertens 2005; 23:1971–1977.

30. Scheltens T, Bots ML, Numans ME, Grobbee DE, Hoes AW. Awareness, treatment and control of hypertension: the ‘rule of halves’ in an era of risk-based treatment of hypertension. J Hum Hypertens 2007; 21:99–106.

31. Zdrojewski T, Szpakowski P, Bandosz P, Pajak A, Wiecek A, Krupa-Wojciechowska B, Wyrzykowski B. Arterial hypertension in Poland in 2002. J Hum Hypertens 2004; 18:557–562.

32. Cifkova R, Skodova Z, Lanska V, Adamkova V, Novozamska E, Jozifova M, et al. Prevalence, awareness, treatment and control of hypertension in the Czech Republic. Results of two nationwide cross sectional surveys in 1997/1998 and 2000/2001, Czech Post-MONICA Study. J Hum Hypertens 2004; 18:571–579.

33. Scuteri A, Najjar SS, Orru M, Albai G, Strait J, Tarasov KV, et al. Ageand gender-specific awareness, treatment and control of cardiovascular risk factors and subclinical vascular lesions in a founder population: the Sardinia Study. Nutr Metab Cardiovasc Dis 2009; 19:532–541.

34. Kastarinen M, Antikainen R, Peltonen M, Laatikainen T, Barengo NC, Jula A, et al. Prevalence, awareness and treatment of hypertension in Finland during 1982–2007. J Hypertens 2009; 27:1552–1559.

35. Falaschetti E, Chaudhury M, Mindell J, Poulter N. Continued improvement in hypertension management in England: results from the Health Survey for England 2006. Hypertension 2009; 53:480–486.

36. Erem C, Hacihasanoglu A, Kocak M, Deger O, Topbas M. Prevalence of prehypertension and hypertension and associated risk factors among Turkish adults: Trabzon Hypertension Study. J Public Health (Oxf) 2009; 31:47–58.

37. Costanzo S, Di Castelnuovo A, Zito F, Krogh V, Siani A, Arnout J, et al. Prevalence, awareness, treatment and control of hypertension in healthy unrelated male-female pairs of European regions: the dietary habit profile in European communities with different risk of myocardial infarction: the impact of migration as a model of geneenvironment interaction project. J Hypertens 2008; 26:2303–2311.

38. Cooper RS. Using public health indicators to measure the success of hypertension control. Hypertension 2007; 49:773–774.

39. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada and the United States. JAMA 2003; 289:2363–2369.

40. Redon J, Olsen MH, Cooper RS, Zurriaga O, Martinez-Beneito MA, Laurent S, et al. Stroke mortality trends from 1990 to 2006 in 39 countries from Europe and Central Asia: implications for control of high blood pressure. Eur Heart J 2011; 32:1424–1431.

41. Pyorala K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1994; 15:1300–1331.

42. D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117:743–753.

43. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation often-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24:987–1003.

44. Woodward M, Brindle P, Tunstall-Pedoe H. Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC). Heart 2007; 93:172–176.

45. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A, Brindle P. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 2008;336:1475–1482.

46. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation 2002; 105:310–315.

47. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 2008; 118:2243–2251; 2244p following 2251.

48. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007;297:611–619.

49. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascular risk: a review for physicians. J Am Coll Cardiol 2009; 54:1209–1227.

50. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2012; 33:1635–1701.

51. Sehestedt T, Jeppesen J, Hansen TW, Wachtell K, Ibsen H, Torp-Pedersen C, et al. Risk prediction is improved by adding markers of subclinical organ damage to SCORE. Eur Heart J 2010; 31:883–891.

52. Sehestedt T, Jeppesen J, Hansen TW, Rasmussen S, Wachtell K, Ibsen H, et al. Thresholds for pulse wave velocity, urine albumin creatinine ratio and left ventricular mass index using SCORE, Framingham and ESH/ESC risk charts. J Hypertens 2012; 30:1928–1936.

53. Volpe M, Battistoni A, Tocci G, Agabiti Rosei E, Catapano AL, Coppo R, et al. Cardiovascular risk assessment beyond systemic coronary risk estimation: a role for organ damage markers. J Hypertens 2012; 30:1056–1064.

54. Guidelines Sub committee 1999. World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17:151–183.

55. World Health Organization, International Society of Hypertension Writing Group. World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21:1983–1992.

56. O’Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001; 322:531–536.

57. Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Compbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and metaanalysis. Lancet 2012; 379:905–914.

58. Fedorowski A, Stavenow L, Hedblad B, Berglund G, Nilsson PM, Melander O. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project). Eur Heart J 2010; 31:85–91.

59. Fagard RH, De Cort P. Orthostatic hypotension is a more robust predictor of cardiovascular events than night-time reverse dipping in elderly. Hypertension 2010; 56:56–61.

60. Trazzi S, Mutti E, Frattola A, Imholz B, Parati G, Mancia G. Reproducibility of noninvasive and intra-arterial blood pressure monitoring: implications for studies on antihypertensive treatment. J Hypertens 1991; 9:115–119.

61. Myers MG, Godwin M, Dawes M, Kiss A, Tobe SW, Kaczorowski J. Measurement of blood pressure in the office: recognizing the problem and proposing the solution. Hypertension 2010; 55:195–200.

62. Julius S, Palatini P, Kjeldsen SE, Zanchetti A, Weber MA, McInnes GT, et al. Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension. Am J Cardiol 2012;109:685–692.

63. Benetos A, Rudnichi A, Thomas F, Safar M, Guize L. Influence of heart rate on mortality in a French population: role of age, gender and blood pressure. Hypertension 1999; 33:44–52.

64. O’Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, et al. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens 2005; 23:697–701.

65. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al., on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013; in press.

66. Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al. European Society of Hypertension practice guidelines for home blood pressure monitoring. J Hum Hypertens 2010; 24:779–785.

67. Parati G, Stergiou GS, Asmar R, Bilo G, de Leeuw P, Imai Y, et al., European Societyof Hypertension Working Groupon Blood Pressure Monitoring. European Society of Hypertension guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring. J Hypertens 2008; 26:1505–1526.

68. Mancia G, Omboni S, Parati G, Trazzi S, Mutti E. Limited reproducibility of hourly blood pressure values obtained by ambulatory blood pressure monitoring: implications for studies on antihypertensive drugs. J Hypertens 1992; 10:1531–1535.

69. Di Rienzo M, Grassi G, Pedotti A, Mancia G. Continuous vs intermittent blood pressure measurements in estimating 24-h average blood pressure. Hypertension 1983; 5:264–269.

70. Stergiou GS, Kollias A, Destounis A, Tzamouranis D. Automated blood pressure measurement in atrial fibrillation: a systematic review and meta-analysis. J Hypertens 2012; 30:2074–2082.

71. Fagard R, Brguljan J, Thijs L, Staessen J. Prediction of the actual awake and asleep blood pressures by various methods of 24 h pressure analysis. J Hypertens 1996; 14:557–563.

72. Octavio JA, Contreras J, Amair P, Octavio B, Fabiano D, Moleiro F, et al. Time-weighted vs. conventional quantification of 24-h average systolic and diastolic ambulatory blood pressures. J Hypertens 2010; 28:459–464.

73. Omboni S, Parati G, Palatini P, Vanasia A, Muiesan ML, Cuspidi C, Mancia G. Reproducibility and clinical value of nocturnal hypotension: prospective evidence from the SAMPLE study. Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation. J Hypertens 1998; 16:733–738.

74. Stenehjem AE, Os I. Reproducibility of blood pressure variability, white-coat effect and dipping pattern in untreated, uncomplicated and newly diagnosed essential hypertension. Blood Press 2004; 13:214–224.

75. Mancia G. Short- and long-term blood pressure variability: present and future. Hypertension 2012; 60:512–517.

76. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003; 107:1401–1406.

77. Head GA, Chatzivlastou K, Lukoshkova EV, Jennings GL, Reid CM. A novel measure of the power of the morning blood pressure surge from ambulatory blood pressure recordings. Am J Hypertens 2010; 23:1074–1081.

78. White WB. Blood pressure load and target organ effects in patients with essential hypertension. J Hypertens 1991; 9 (Suppl 8):S39–S41.

79. Li Y, Wang JG, Dolan E, Gao PJ, Guo HF, Nawrot T, et al. Ambulatory arterial stiffness index derived from 24-h ambulatory blood pressure monitoring. Hypertension 2006; 47:359–364.

80. Parati G, Schillaci G. What are the real determinants of the ambulatory arterial stiffness index? J Hypertens 2012; 30:472–476.

81. Verdecchia P, Angeli F, Mazzotta G, Garofoli M, Ramundo E, Gentile G, et al. Day-night dip and early-morning surge in blood pressure in hypertension: prognostic implications. Hypertension 2012; 60:34–42.

82. Gaborieau V, Delarche N, Gosse P. Ambulatory blood pressure monitoring vs. self-measurement of blood pressure at home: correlation with target organ damage. J Hypertens 2008; 26:1919–1927.

83. Bliziotis IA, Destounis A, Stergiou GS. Home vs. ambulatory and office blood pressure in predicting target organ damage in hypertension: a systematic review and meta-analysis. J Hypertens 2012; 30:1289–1299.

84. Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA 1999; 282:539–546.

85. Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, et al., Office vs. Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003; 348:2407–2415.

86. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension 2005; 46:156–161.

87. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005; 111:1777–1783.

88. Conen D, Bamberg F. Noninvasive 24-h ambulatory blood pressure and cardiovascular disease: a systematic review and meta-analysis. J Hypertens 2008; 26:1290–1299.

89. Boggia J, Li Y, Thijs L, Hansen TW, Kikuya M, Bjorklund-Bodegard K, et al. Prognostic accuracy of day vs. night ambulatory blood pressure: a cohort study. Lancet 2007; 370:1219–1229.

90. Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and night-time blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008; 51:55–61.

91. Fagard RH, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Prognostic significance of ambulatory blood pressure in hypertensive patients with history of cardiovascular disease. Blood Press Monit 2008; 13:325–332.

92. Minutolo R, Agarwal R, Borrelli S, Chiodini P, Bellizzi V, Nappi F, et al. Prognostic role of ambulatory blood pressure measurement in patients with nondialysis chronic kidney disease. Arch Intern Med 2011; 171:1090–1098.

93. de la Sierra A, Banegas JR, Segura J, Gorostidi M, Ruilope LM. Ambulatory blood pressure monitoring and development of cardiovascular events in high-risk patients included in the Spanish ABPM registry: the CARDIORISC Event study. J Hypertens 2012; 30:713–719.

94. Hansen TW, Li Y, Boggia J, Thijs L, Richart T, Staessen JA. Predictive role of the night-time blood pressure. Hypertension 2011; 57:3–10.

95. Fagard RH, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Night-day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension. J Hum Hypertens 2009; 23:645–653.

96. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Trevano FQ, et al. Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. Hypertension 2007; 49:1265–1270.

97. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001; 38:852–857.

98. Parati G, Omboni S. Role of home blood pressure telemonitoring in hypertension management: an update. Blood Press Monit 2010; 15:285–295.

99. Stergiou GS, Nasothimiou EG. Hypertension: Does home telemonitoring improve hypertension management? Nature Rev Nephrol 2011; 7:493–495.

100. Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, et al. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama study. Hypertension 2008; 52:1045–1050.

101. Stergiou GS, Bliziotis IA. Home blood pressure monitoring in the diagnosis and treatment of hypertension: a systematic review. Am J Hypertens 2011; 24:123–134.

102. Stergiou GS, Siontis KC, Ioannidis JP. Home blood pressure as a cardiovascular outcome predictor: it’s time to take this method seriously. Hypertension 2010; 55:1301–1303.

103. Ward AM, Takahashi O, Stevens R, Heneghan C. Home measurement of blood pressure and cardiovascular disease: systematic review and meta-analysis of prospective studies. J Hypertens 2012; 30:449–456. 104. Fagard RH, Van Den Broeke C, De Cort P. Prognostic significance of blood pressure measured in the office, at home and during ambulatory monitoring in older patients in general practice. J Hum Hypertens 2005; 19:801–807.

105. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home and ambulatory blood pressure. Hypertension 2006; 47:846–853.

106. Mancia G, Bertinieri G, Grassi G, Parati G, Pomidossi G, Ferrari A, et al. Effects of blood-pressure measurement by the doctor on patient’s blood pressure and heart rate. Lancet 1983; 2:695–698.

107. Parati G, Ulian L, Santucciu C, Omboni S, Mancia G. Difference between clinic and daytime blood pressure is not a measure of the white-coat effect. Hypertension 1998; 31:1185–1189.

108. Mancia G, Zanchetti A. White-coat hypertension: misnomers, misconceptions and misunderstandings. What should we do next? J Hypertens 1996; 14:1049–1052.

109. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: a meta-analysis. J Hypertens 2007; 25:2193–2198.

110. Staessen JA, O’Brien ET, Amery AK, Atkins N, Baumgart P, De Cort P, et al. Ambulatory blood pressure in normotensive and hypertensive subjects: results from an international database. J Hypertens Suppl 1994; 12:S1–12.

111. Dolan E, Stanton A, Atkins N, Den Hond E, Thijs L, McCormack P, et al. Determinants of white-coat hypertension. Blood Press Monit 2004; 9:307–309.

112. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an updated meta analysis. Am J Hypertens 2011; 24:52–58.

113. Franklin SS, Thijs L, Hansen TW, Li Y, Boggia J, Kikuya M, et al. Significance of white-coat hypertension in older persons with isolated systolic hypertension: a meta-analysis using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes population. Hypertension 2012; 59:564–571.

114. Sega R, Trocino G, Lanzarotti A, Carugo S, Cesana G, Schiavina R, et al. Alterations of cardiac structure in patients with isolated office, ambulatory, or home hypertension: Data from the general population (Pressione Arteriose Monitorate E Loro Associazioni [PAMELA] Study). Circulation 2001; 104:1385–1392.

115. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Grassi G, Sega R. Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension. J Hypertens 2009; 27:1672–1678.

116. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, et al. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension 2009; 54:226–232.

117. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008; 26:1715–1725.

118. Ogedegbe G, Agyemang C, Ravenell JE. Masked hypertension: evidence of the need to treat. Current Hypertens Rep 2010; 12:349– 355.

119. Lurbe E, Torro I, Alvarez V, Nawrot T, Paya R, Redon J, Staessen JA. Prevalence, persistence and clinical significance of masked hypertension in youth. Hypertension 2005; 45:493–498.

120. Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347:797–805.

121. Wijkman M, Lanne T, Engvall J, Lindstrom T, Ostgren CJ, Nystrom FH. Masked nocturnal hypertension: a novel marker of risk in type 2 diabetes. Diabetologia 2009; 52:1258–1264.

122. Hodgkinson J, Mant J, Martin U, Guo B, Hobbs FD, Deeks JJ, et al. Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review. BMJ 2011; 342:d3621.

123. Fagard R, Grassi G. Blood pressure response to acute physical and mental stress. In: Mancia G, Grassi G, Kjeldsen SE, editors. Manual of Hypertension of the European Societyof Hyper- tension. London, UK: Informa Healthcare; 2008. pp. 184–189.

124. Le VV, Mitiku T, Sungar G, Myers J, Froelicher V. The blood pressure response to dynamic exercise testing: a systematic review. Prog Cardiovasc Dis 2008; 51:135–160.

125. Smith RG, Rubin SA, Ellestad MH. Exercise hypertension: an adverse prognosis? J Am Soc Hyper 2009; 3:366–373.

126. Huot M, Arsenault BJ, Gaudreault V, Poirier P, Perusse L, Tremblay A, et al. Insulin resistance low cardiorespiratory fitness increased exercise blood pressure: contribution of abdominal obesity. Hypertension 2011; 58:1036–1042.

127. Sung J, Choi SH, Choi YH, Kim DK, Park WH. The relationship between arterial stiffness and increase in blood pressure during exercise in normotensive persons. J Hypertens 2012; 30:587–591.

128. Holmqvist L, Mortensen L, Kanckos C, Ljungman C, Mehlig K, Manhem K. Exercise blood pressure and the risk of future hypertension. J Hum Hypertens 2012; 26:691–695.

129. Fagard RH, Pardaens K, Staessen JA, Thijs L. Prognostic value of invasive haemodynamic measurements at restand during exercise in hypertensive men. Hypertension 1996; 28:31–36.

130. Kjeldsen SE, Mundal R, Sandvik L, Erikssen G, Thaulow E, Erikssen J. Supine and exercise systolic blood pressure predict cardiovascular death in middle-aged men. J Hypertens 2001; 19:1343–1348.

131. Sharman JE, Hare JL, Thomas S, Davies JE, Leano R, Jenkins C, Marwick TH. Association of masked hypertension and left ventricular remodeling with the hypertensive response to exercise. Am J Hypertens 2011; 24:898–903.

132. Hedberg P, Ohrvik J, Lonnberg I, Nilsson G. Augmented blood pressure response to exercise is associated with improved long-term survival in older people. Heart 2009; 95:1072–1078.

133. Gupta MP, Polena S, Coplan N, Panagopoulos G, Dhingra C, Myers J, Froelicher V. Prognostic significance of systolic blood pressure increases in men during exercise stress testing. Am J Cardiol 2007; 100:1609–1613.

134. Corra U, Giordano A, Mezzani A, Gnemmi M, Pistono M, Caruso R, Giannuzzi P. Cardiopulmonary exercise testing and prognosis in heart failure due to systolic left ventricular dysfunction: a validation study of the European Society of Cardiology Guidelines and Recommendations (2008) and further developments. Eur J Prev Cardiol 2012; 19:32–40.

135. Carroll D, Phillips AC, Der G, Hunt K, Benzeval M. Blood pressure reactions to acute mental stress and future blood pressure status: data from the 12-year follow-up of the West of Scotland Study. Psychosom Med 2011; 73:737–742.

136. Chida Y, Steptoe A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status: a meta-analysis of prospective evidence. Hypertension 2010; 55:1026–1032.

137. Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries; Theoretical, experimental and clinical principles, Fifth Edition Oxford: Oxford University Press; 2005; p. 624.

138. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27:2588–2605.

139. Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, Guyonvarc’h PM, London GM. Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002; 39:735–738.

140. Vlachopoulos C, Aznaouridis K, O’Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 2010; 31:1865–1871.

141. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. Re-appraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27:2121–2158.

142. O’Rourke MF, Adji A. Guidelines on guidelines: focus on isolated systolic hyprtension in youth. J Hypertens 2013; 31:649–654.

143. Hunt SC, Williams RR, Barlow GK. A comparison of positive family history definitions for defining risk of future disease. J Chronic Dis 1986; 39:809–821.

144. Friedman GD, Selby JV, Quesenberry CP Jr, Armstrong MA, Klatsky AL. Precursors of essential hypertension: body weight, alcohol and salt use and parental history of hypertension. Prev Med 1988; 17:387–402.

145. Luft FC. Twins in cardiovascular genetic research. Hypertension 2001;37:350–356.

146. Fagard R, Brguljan J, Staessen J, Thijs L, Derom C, Thomis M, Vlietinck R. Heritability of conventional and ambulatory blood pressures. A study in twins. Hypertension 1995; 26:919–924.

147. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell 2001; 104:545–556.

148. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; 478:103–109.

149. Levy D, Salomon M, D’Agostino RB, Belanger AJ, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994; 90:1786–1793.

150. Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004; 292:2343–2349.

151. Fagard RH, Staessen JA, Thijs L, Celis H, Birkenhager WH, Bulpitt CJ, et al. Prognostic significance of electrocardiographic voltages and their serial changes in elderly with systolic hypertension. Hypertension 2004; 44:459–464.

152. Okin PM, Oikarinen L, Viitasalo M, Toivonen L, Kjeldsen SE, Nieminen MS, et al. Prognostic value of changes in the electrocardiographic strain pattern during antihypertensive treatment: the Losartan Intervention for End-Point Reduction in Hypertension Study (LIFE). Circulation 2009; 119:1883–1891.

153. Kirchhof P, Bax J, Blomstrom-Lundquist C, Calkins H, Camm AJ, Cappato R, et al. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‘research perspectives in AF’. Eur Heart J 2009; 30:2969–2977c.

154. Kirchhof P, Lip GY, Van Gelder IC, Bax J, Hylek E, Kaab S, et al. Comprehensive risk reduction in patients with atrial fibrillation: Emerging diagnostic and therapeutic options. Executive summary of the report from the 3rd AFNET/EHRA consensus conference. Thromb Haemost 2011; 106:1012–1019.

155. Reichek N, Devereux RB. Left ventricular hypertrophy: relationship of anatomic, echocardiographic and electrocardiographic findings. Circulation 1981; 63:1391–1398.

156. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322:1561–1566.

157. Tsioufis C, Kokkinos P, Macmanus C, Thomopoulos C, Faselis C, Doumas M, et al. Left ventricular hypertrophy as a determinant of renal outcome in patients with high cardiovascular risk. J Hypertens 2010; 28:2299–2308.

158. Cuspidi C, Ambrosioni E, Mancia G, Pessina AC, Trimarco B, Zanchetti A. Role of echocardiography and carotid ultrasonography in stratifying risk in patients with essential hypertension: the Assessment of Prognostic Risk Observational Survey. J Hypertens 2002; 20:1307–1314.

159. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7:79–108.

160. Chirinos JA, Segers P, De Buyzere ML, Kronmal RA, Raja MW, De Bacquer D, et al. Left ventricular mass: allometric scaling, normative values, effect of obesity and prognostic performance. Hypertension 2010; 56:91–98.

161. Armstrong AC, Gidding S, Gjesdal O, Wu C, Bluemke DA, Lima JA. LV mass assessed by echocardiography and CMR, cardiovascular outcomes and medical practice. JACCCardiovasc Imaging 2012; 5:837–848.

162. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352.

163. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Bartoccini C, et al. Adverse prognostic significance of concentric remodeling of the left ventricle in hypertensive patients with normal left ventricular mass. J Am Coll Cardiol 1995; 25:871–878.

164. Muiesan ML, Salvetti M, Monteduro C, Bonzi B, Paini A, Viola S, et al. Left ventricular concentric geometry during treatment adversely affects cardiovascular prognosis in hypertensive patients. Hypertension 2004; 43:731–738.

165. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function: epidemiology, clinical characteristics and prognosis. J Am Coll Cardiol 2004; 43:317–327.

166. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001; 37:1042–1048.

167. Bella JN, Palmieri V, Roman MJ, Liu JE, Welty TK, Lee ET, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study. Circulation 2002; 105:1928–1933.

168. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009; 10:165–193.

169. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003; 289:194–202.

170. De Sutter J, De Backer J, Van de Veire N, Velghe A, De Buyzere M, Gillebert TC. Effects of age, gender and left ventricular mass on septal mitral annulus velocity (E0) and the ratio of transmitral early peak velocity to E0 (E/E0). Am J Cardiol 2005; 95:1020–1023.

171. Sharp AS, Tapp RJ, Thom SA, Francis DP, Hughes AD, Stanton AV, et al. Tissue Doppler E/E0ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT sub-study. Eur Heart J 2010; 31:747–752.

172. Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ, Tsang TS. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol 2006; 47:2357–2363.

173. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr 2011; 12:167–205.

174. Galderisi M, Lomoriello VS, Santoro A, Esposito R, Olibet M, Raia R, et al. Differences of myocardial systolic deformation and correlates of diastolic function in competitive rowers and young hypertensives: a speckle-tracking echocardiography study. J Am Soc Echocardiogr 2010; 23:1190–1198.

175. Codella NC, Lee HY, Fieno DS, Chen DW, Hurtado-Rua S, Kochar M, et al. Improved left ventricular mass quantification with partial voxel interpolation: in vivo and necropsy validation of a novel cardiac MRI segmentation algorithm. Circ Cardiovasc Imaging 2012; 5:137–146.

176. Parsai C, O’Hanlon R, Prasad SK, Mohiaddin RH. Diagnostic and prognostic value of cardiovascular magnetic resonance in nonischaemic cardiomyopathies. J Cardiovasc Magn Reson 2012; 14:54.

177. Picano E, Palinkas A, Amyot R. Diagnosis of myocardial ischemia in hypertensive patients. J Hypertens 2001; 19:1177–1183.

178. Chin D, Battistoni A, Tocci G, Passerini J, Parati G, Volpe M. Noninvasive diagnostic testing for coronary artery disease in the hypertensive patient: potential advantages of a risk estimation-based algorithm. Am J Hypertens 2012; 25:1226–1235.

179. Schulman DS, Francis CK, Black HR, Wackers FJ. Thallium-201 stress imaging in hypertensive patients. Hypertension 1987; 10:16–21.

180. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, et al. Stress Echocardiography Expert Consensus Statement: Executive Summary: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur Heart J 2009; 30:278–289.

181. Greenwood JP, Maredia N, Younger JF, Brown JM, Nixon J, Everett CC, et al. Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Lancet 2012; 379:453–460.

182. Cortigiani L, Rigo F, Galderisi M, Gherardi S, Bovenzi F, Picano E, Sicari R. Diagnostic and prognostic value of Doppler echocardiographic coronary flow reserve in the left anterior descending artery in hypertensive and normotensive patients [corrected]. Heart 2011; 97:1758–1765.

183. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997; 96:1432–1437.

184. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999; 340:14–22.

185. Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol 2010; 55:1600–1607.

186. Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palu C, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002; 106:2422–2427.

187. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Desvarieux M, et al. Mannheim intima-media thickness consensus. Cerebrovasc Dis 2004; 18:346–349.

188. Zanchetti A, Hennig M, Hollweck R, Bond G, Tang R, Cuspidi C, et al. Baseline values but nottreatment-induced changes in carotid intimamediathickness predict incident cardiovascular events in treated hypertensive patients: findings in the European Lacidipine Study on Atherosclerosis (ELSA). Circulation 2009; 120:1084–1090.

189. Peters SA, den Ruijter HM, Bots ML, Moons KG. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart 2012; 98:177–184.

190. Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003; 107:2864–2869.

191. Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens 2012; 30:445–448.

192. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37:1236–1241.

193. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327.

194. Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002; 39:10–15.

195. Mattace-Raso FU, vander Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006; 113:657–663.

196. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010; 121:505–511.

197. Feringa HH, Bax JJ, van Waning VH, Boersma E, Elhendy A, Schouten O, et al. The long-term prognostic value of the resting and postexercise ankle-brachial index. Arch Intern Med 2006; 166:529–535.

198. Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008; 300:197–208.

199. De Buyzere ML, Clement DL. Management of hypertension in peripheral arterial disease. Prog Cardiovasc Dis 2008; 50:238–263.

200. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens 2001; 19:921–930.

201. Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002; 106:3037–3043.

202. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, et al. Prognostic significance of small-artery structure in hypertension. Circulation 2003; 108:2230–2235.

203. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2010; 122:e584–e636.

204. Perrone-Filardi P, Achenbach S, Mohlenkamp S, Reiner Z, Sambuceti G, Schuijf JD, et al. Cardiac computed tomography and myocardial perfusion scintigraphy for risk stratification in asymptomatic individuals without known cardiovascular disease: a position statement of the Working Group on Nuclear Cardiology and Cardiac CT of the European Society of Cardiology. Eur Heart J 2011; 32:1986–1993.

205. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005; 111:363–368.

206. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 2009; 32 (Suppl 2):S314–321.

207. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function: measured and estimated glomerular filtration rate. N Engl J Med 2006; 354:2473–2483.

208. Hallan S, Asberg A, Lindberg M, Johnsen H. Validation of the Modification of Diet in Renal Disease formula for estimating GFR with special emphasis on calibration of the serum creatinine assay. Am J Kidney Dis 2004; 44:84–93.

209. Matsushita K, Mahmodi BK, Woodward M, Emberson JM, Jafar JH, Jee SH, et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estmated glomerular filtration rate. JAMA 2012; 307:1941–1951.

210. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005; 67:2089–2100.

211. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Definition, evaluation and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69:1945–1953.

212. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, et al. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med 2006; 145:237–246.

213. Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999; 56:2214–2219.

214. Parving HH. Initiation and progression of diabetic nephropathy. N Engl J Med 1996; 335:1682–1683.

215. Ruilope LM, Rodicio JL. Clinical relevance of proteinuria and microalbuminuria. Curr Opin Nephrol Hypertens 1993; 2:962–967.

216. Redon J, Williams B. Microalbuminuria in essential hypertension: redefining the threshold. J Hypertens 2002; 20:353–355.

217. Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K. Arterial hypertension, microalbuminuria and risk of ischemic heart disease. Hypertension 2000; 35:898–903.

218. de Leeuw PW, Ruilope LM, Palmer CR, Brown MJ, Castaigne A, Mancia G, et al. Clinical significance of renal function in hypertensive patients at high risk: results from the INSIGHT trial. Arch Intern Med 2004; 164:2459–2464.

219. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology and Epidemiology and Prevention. Circulation 2003; 108:2154–2169.

220. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. Albuminuria and risk of cardiovascular events, death and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286:421–426.

221. Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003; 139:901–906.

222. Jager A, Kostense PJ, Ruhe HG, Heine RJ, Nijpels G, Dekker JM, et al. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Arterioscler Thromb Vac Biol 1999; 19:617–624.

223. Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens 1998; 16:1325–1333.

224. National Kidney Foundation. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Executive summary. Am J Kid Dis 2004; 43 (Suppl 1):S16–S33.

225. Arnlov J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, et al. Lowgrade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 2005; 112:969–975.

226. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106:1777–1782.

227. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009; 20:1813–1821.

228. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375:2073–2081.

229. Zanchetti A, Hansson L, Dahlof B, Elmfeldt D, Kjeldsen S, Kolloch R, et al. Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group. J Hypertens 2001; 19:1149–1159.

230. Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, Zanchetti A. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 2001; 12:218–225.

231. De Leeuw PW, Thijs L, Birkenhager WH, Voyaki SM, Efstratopoulos AD, Fagard RH, et al. Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur trial. J Am Soc Nephrol 2002; 13:2213–2222.

232. Segura J, Ruilope LM, Zanchetti A. On the importance of estimating renal function for cardiovascular risk assessment. J Hypertens 2004; 22:1635–1639.

233. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, et al. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 2006; 144:172–180.

234. Breslin DJ, Gifford RW Jr, Fairbairn JF 2nd, Kearns TP. Prognostic importance of ophthalmoscopic findings in essential hypertension. JAMA 1966; 195:335–338.

235. Frant R, Groen J. Prognosis of vascular hypertension; a 9 year followup study of 418 cases. Arch Intern Med (Chic) 1950; 85:727–750.

236. Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med 2004; 351:2310–2317.

237. Sairenchi T, Iso H, Yamagishi K, Irie F, Okubo Y, Gunji J, et al. Mild retinopathy is a risk factor for cardiovascular mortality in Japanese with and without hypertension: the Ibaraki Prefectural Health Study. Circulation 2011; 124:2502–2511.

238. Mollentze WF, Stulting AA, Steyn AF. Ophthalmoscopy vs. nonmydriaticfundus photography inthe detection ofdiabetic retinopathy in black patients. SAfr Medj 1990; 78:248–250.

239. Dimmitt SB, West JN, Eames SM, Gibson JM, Gosling P, Littler WA. Usefulness of ophthalmoscopy in mild to moderate hypertension. Lancet 1989; 1:1103–1106.

240. van den Born BJ, Hulsman CA, Hoekstra JB, Schlingemann RO, van Montfrans GA. Value of routine funduscopy in patients with hypertension: systematic review. BMJ 2005; 331:73.

241. McGeechan K, Liew G, Macaskill P, Irwig L, Klein R, Klein BE, et al. Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. Am J Epidemiol 2009; 170:1323–1332.

242. Antonios TF, Singer DR, Markandu ND, Mortimer PS, Mac Gregor GA. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension 1999; 34:655–658.

243. Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV, Watt GC. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997; 99:1873–1879.

244. Cuspidi C, Meani S, Salerno M, Fusi V, Severgnini B, Valerio C, et al. Retinal microvascular changes and target organ damage in untreated essential hypertensives. J Hypertens 2004; 22:2095–2102.

245. Hubbard LD, Brothers RJ, King WN, Clegg LX, Klein R, Cooper LS, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999; 106:2269–2280.

246. Ikram MK, de Jong FJ, Vingerling JR, Witteman JC, Hofman A, Breteler MM, de Jong PT. Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 2004; 45:2129–2134.

247. Wong TY, Knudtson MD, Klein R, Klein BE, Meuer SM, Hubbard LD. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes and effect of refractive errors. Ophthalmology 2004; 111:1183–1190.

248. Sun C, Liew G, Wang JJ, Mitchell P, Saw SM, Aung T, et al. Retinal vascular caliber, blood pressure and cardiovascular risk factors in an Asian population: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci 2008; 49:1784–1790.

249. Lehmann MV, Schmieder RE. Remodeling of retinal small arteries in hypertension. Am J Hypertens 2011; 24:1267–1273.

250. Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996; 27:1274–1282.

251. de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, Breteler MM. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002; 125:765–772.

252. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurology 2007; 6:611–619.

253. Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, et al. Cerebral white matter lesions, retinopathy and incident clinical stroke. JAMA 2002; 288:67–74.

254. Buyck JF, Dufouil C, Mazoyer B, Maillard P, Ducimetiere P, Alperovitch A, et al. Cerebral white matter lesions are associated with the risk of stroke but not with other vascular events: the 3-City Dijon Study. Stroke 2009; 40:2327–2331.

255. Kearney-Schwartz A, Rossignol P, Bracard S, Felblinger J, Fay R, Boivin JM, et al. Vascular structure and function is correlated to cognitive performance and white matter hyperintensities in older hypertensive patients with subjective memory complaints. Stroke 2009; 40:1229–1236.

256. Henskens LH, van Oostenbrugge RJ, Kroon AA, Hofman PA, Lodder J, de Leeuw PW. Detection of silent cerebrovascular disease refines risk stratification of hypertensive patients. J Hypertens 2009; 27:846– 853.

257. Stewart R, Xue QL, Masaki K, Petrovitch H, Ross GW, White LR, Launer LJ. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension 2009; 54:233–240.

258. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L. Persson G, Oden A, Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet 1996; 347:1141–1145.

259. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension 1998; 31:780–786.

260. Collins R, Mac Mahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994; 50:272–298.

261. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 2004; 292:2350–2356.

262. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45:198–202.

263. Sytkowski PA, D’Agostino RB, Belanger AJ, Kannel WB. Secular trends in long-term sustained hypertension, long-term treatment and cardiovascular mortality. The Framngham Heart Study 1950 to 1990. Circulation 1996; 93:697–703.

264. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension 2003; 42:1206–1252.

265. Zanchetti A, Grassi G, Mancia G. When should antihypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical re-appraisal. J Hypertens 2009; 27:923–934.

266. Medical Research Council Working Party. MRC trial on treatment of mild hypertension: principal results. Br Med J 1985; 291:97–104.

267. Management Committee. The Australian therapeutic trial in mild hypertension. Lancet 1980; 1:1261–1267.

268. Hypertension Detection and Follow-up Program Cooperative Group. The effect of treatment on mortality in ‘mild’ hypertension: results of the Hypertension Detection and Follow- up Program. N Engl J Med 1982; 307:976–980.

269. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebocontrolled trial in Chinese hypertensive patients. J Hypertens 2005; 23:2157–2172.

270. Zhang Y, Zhang X, Liu L, Zanchetti A. Is a systolic blood pressure target <140mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial. Eur Heart J 2011; 32:1500–1508.

271. National Institute for Health and Clinical Excellence. Hypertension (CG127): clinical management of primary hypertension in adults. http://www.nice.org.uk/guidance/CG127.