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1 대한내과학회지 : 제 85 권제 1 호 고혈압환자에서혈압변동성및심장박동수와 hscrp 와의연관성 단국대학교의과대학심장혈관내과학교실 김동민 임성훈 이명용 Relationship of Blood Pressure Variability and Heart Rate with Plasma hscrp in Patients with Recently Diagnosed Hypertension Dongmin Kim, Seong-Hoon Lim, and Myung-Yong Lee Division of Cardiology, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea Background/Aims: Blood pressure (BP) variability and heart rate (HR) are associated with target organ damage and cardiovascular complications; however, the exact mechanisms are uncertain. In this study, we examined the association of an inflammatory marker with BP variability and HR. Methods: A total of 151 patients diagnosed recently with hypertension were subjected to 24-h ambulatory BP monitoring. BP variability was assessed as the standard deviation of the BP recordings. The average HR and HR variability were calculated from concomitantly recorded HR values. Plasma high-sensitivity C-reactive protein (hscrp) was used as a marker of inflammation. Results: The mean age of the study population was 44 ± 11.3 years, and 74.2% of the patients were male. The plasma hscrp level was higher in male patients (0.131 ± vs ± 0.023, p = 0.001) and patients with a history of smoking (0.136 ± vs ± 0.017, p = 0.003). A correlation analysis showed that the variability in diastolic BP during 24-h monitoring was associated with hscrp (p = 0.002, r = 0.258). The 24-h (p = 0.004, r = 0.236), daytime (p = 0.003, r = 0.239), and nighttime (p = 0.020, r = 0.190) average HRs were related to the hscrp level. The 24-h HR variability (p = 0.025, r = 0.182) was also associated with hscrp. After adjusting for the effect of related variables, the 24-h diastolic BP variability (β = 0.286, p = 0.011) and daytime average HR (β = 0.169, p = 0.049) were positively related to hscrp. Conclusions: Plasma hscrp is related to diastolic BP variability in recently diagnosed hypertensive patients. Moreover, HR measured with BP is associated with hscrp. These findings suggest that inflammation mediates adverse cardiovascular outcomes of BP variability and an elevated HR. (Korean J Med 2013;85:50-57) Keywords: Ambulatory blood pressure monitoring; Heart rate; C-reactive protein; Hypertension Received: Revised: Accepted: Correspondence to Myung-Yong Lee, M.D. Ph.D. Division of Cardiology, Department of Internal Medicine, Dankook University College of Medicine, 201 Manghyang-ro, Cheonan , Korea Tel: , Fax: , mel_lee@dankook.ac.kr Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Dongmin Kim, et al. BP variability and HR to hscrp - 서 론 Inc, Marbur, Germany) 기기를이용하여측정하였다. 24시간활동성혈압 (24 hour ambulatory blood pressure monitoring) 은고혈압진단에유용한방법이다 [1]. 또한 24시간활동성혈압은진료실혈압보다표적장기손상과더관련이있으며심혈관계위험도좀더잘예측할수있는수단이다 [1]. 이를통하여단순한혈압뿐만아니라혈압의표준편차, 즉혈압의변동성등을확인할수있으며이러한혈압의변동성은혈압의정도와는관계없이표적장기손상및심혈관계합병증과연관이있음이알려져있다 [2-8]. 하지만혈압의변동성과표적장기손상또는심혈관계합병증과의연관성의정확한기전은잘알려져있지않다. 일부연구 [9-11] 에서 C 반응단백질 (C-reactive protein; CRP) 등의염증표지자와혈압변동성과의관계가확인된바있으나일반화하기어려운점이있으며특히한국인에서이와같은연관성이증명된바는없다. 안정시심장박동수는일반인, 고혈압환자등에서심혈관계합병증과연관이있다 [12]. 또한생활심전도를통하여얻은평균심장박동수및심장박동수의변동성은염증표지자등과관련이있다고알려져있다 [13-15]. 하지만 24시간활동성혈압을통하여얻은심장박동수와염증표지자와의관계는잘알려져있지않다. 이에저자들은 24시간활동성혈압을통하여얻어진혈압및심장박동수와 high-sensitivity C-reactive protein (hscrp) 의관계를알아보고자본연구를시행하였다. 대상및방법대상 2006년 1월부터 2011년 12월까지본원에서고혈압이의심되거나최근 3개월이내에고혈압이진단된환자를대상으로이들의 24시간활동성혈압, hscrp 및역학적특징등을후향적으로조사하였다. 24시간활동성혈압을통하여얻은수축기혈압의평균이 130 mmhg 이상인환자를고혈압으로진단하여분석하였고대상자중염증성질환을가지고있거나임신성고혈압등 2차성고혈압환자는제외하였다. 혈중 hscrp 의측정혈중 hscrp 는 Behring nephelometer analyzer II (Dade Behring 24시간활동성혈압및심장박동수의측정 Non-invasive oscillometric system (P6 Pressurometer; Del Mar Reynold, CA, USA) 을이용하여 24시간활동성혈압을측정하였다. 적절한 BP cuff 를주로사용하지않는팔에적용하였고심한신체활동을제외한일상생활을하도록교육하였다. 환자에게일기를쓰도록하여활동시간과수면시간을기록하도록하였으며이를통하여활동시간및수면시간의혈압을추정하였다. 오전 7시부터오후 11시까지는 30분간격으로, 오후 11시부터오전 7시까지는 60분간격으로혈압을측정하였으며모든측정값중오류가 15% 이상이면분석에서제외하였다. 혈압의변동성은 24시간, 활동시간, 수면시간동안측정된수축기및이완기혈압의표준편차로정의하여값을구하였다. 심장박동수는위와같은간격으로혈압을측정할때동시에측정된값으로 24시간, 활동시간, 수면시간등으로나누어평균및표준편차값을계산하였다. 통계분석측정변수들의기술통계량은비연속변수이면 빈도 (%) 로제시하였으며, 연속변수이면 평균 ± 표준편차 로제시하였다. 혈중 hscrp 측정치는중앙값으로나타냈다. 상관분석은변수의정규성에따라 Pearson 및 Spearman correlation을이용하여분석하였으며상관계수 (r) 와 p value를같이표시하였다. 이변량분석에서의미가있거나기존에연관성이알려진변수들을중심으로다중선형회귀분석으로다변량분석을시행하였다. 다중공선성을보이는변수는제외하였으며최종모델에서 tolerance 는 이었다 (variance inflation factor: ). 모든유의성검정은 p < 0.05에서실시하였다. 자료의통계분석은 SPSS version 17.0 for Window (SPSS, Chicago, IL, USA) 를이용하였다. 결과대상환자의임상적특성전체조사대상환자는 151명으로평균연령은 44.5 ± 11.3 세이었고이중남성은 74.2% 이었다. 평균체질량지수는 (Body mass index; BMI) 25.9 ± 3.8 kg/m 2, 평균총콜레스테롤은 ± 34.3 mg/dl 였다. hscrp의중앙값은 0.07 mg/dl (inter

3 - 대한내과학회지 : 제 85 권제 1 호통권제 635 호 quartile range: ) 이었다. 그밖의임상적, 진단검사의학적특징은표 1과같았다. 임상적, 진단검사의학적특징과 hscrp 와의관계 Plasma hscrp는남성에서 (0.131 ± vs ± 0.023, p = 0.001), 흡연력이있는환자군에서 (0.136 ± vs ± 0.017, p = 0.003) 높게나타났다. 대상환자의체질량지수 (r = 0.364, p = 0.001), 혈중 creatinine (r = 0.188, p = 0.021), 총콜레스테롤 (r = 0.166, p = 0.043), 중성지방 (r = 0.270, p = 0.001) 등은 hscrp 와양의상관관계를고밀도지단백은 (r = , p = 0.001) 음의상관관계를보였다 (Table 2). 24 시간활동성혈압및혈압변동성과 hscrp 와의관계 24시간활동성혈압을통하여얻어진평균수축기혈압은 ± 8.7 mmhg, 이완기혈압은 92.5 ± 8.4 mmhg 였고환자개인의수축기혈압의변동성은 14.9 ± 3.9 mmhg, 이완기혈압의변동성은 11.9 ± 2.8 mmhg 였다 (Table 3). 24시간동안의수축기혈압, 수축기혈압의변동성및이완기혈압은 hscrp와연관성을보이지않았으나이완기혈압의변동성은 hscrp와양의상관관계를보였다 (r = 0.258, p = 0.002) Table 1. Demographic and laboratory characteristics of the study population (n = 151) Data Age, yr 44.5 ± 11.3 Males, % 74.2 BMI, kg/m ± 3.8 Family history of CVD, % 11.4 Family history of HTN, % 53.7 Smoking, % 57.7 Fasting glucose, mg/dl 98.6 ± 24.6 Serum creatinine, mg/dl 0.89 ± 0.27 Total cholesterol, mg/dl ± 34.3 Triglycerides, mg/dl ± LDL-C, mg/dl ± 29.8 HDL-C, mg/dl 48.3 ± 14.2 Median hscrp, mg/dl 0.07 ( ) (interquartile range) BMI, body mass index; CVD, cerebrovascular disease; HTN, hypertension; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hscrp, high-sensitivity C- reactive protein. Table 2. Relationship between demographic and laboratory variables and hscrp hscrp p (r) Age (0.013) Sex (N.A.) b BMI (0.364) Smoking (N.A.) b Fasting glucose (0.084) a Serum creatinine (0.188) Total cholesterol (0.166) Triglycerides (0.270) LDL-C (0.082) HDL-C (-0.262) hscrp, high-sensitivity C-reactive protein; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; HDL-C, highdensity lipoprotein cholesterol; N.A., not applicable. a Spearman correlation. b Mann-Whitney U test. Table 3. Ambulatory BP and HR parameters of the study population Mean ± SD Systolic BP, mmhg Twenty-four hour ± 8.7 Daytime ± 8.9 Nighttime ± 12.0 Twenty-four hour within-subject SD 14.9 ± 3.9 Daytime within-subject SD 13.4 ± 3.9 Nighttime within-subject SD 10.6 ± 4.9 Diastolic BP, mmhg Twenty-four hour 92.5 ± 8.4 Daytime 95.0 ± 8.7 Nighttime 82.6 ± 9.7 Twenty-four hour within-subject SD 11.9 ± 2.8 Daytime within-subject SD 10.7 ± 2.7 Nighttime within-subject SD 9.4 ± 3.9 HR (BPM) Twenty-four hour 75.0 ± 8.9 Daytime 77.7 ± 9.5 Nighttime 64.5 ± 8.5 Twenty-four hour within-subject SD 10.9 ± 3.3 Daytime within-subject SD 9.8 ± 3.1 Nighttime within-subject SD 6.5 ± 3.3 SD, standard deviation; BP, blood pressure; HR, heart rate; BPM, beats per minute

4 - 김동민외 2 인. 혈압변동성및심장박동수와 hscrp - Table 4. Bivariate correlation analysis of hscrp and ambulatory BP and HR variables hscrp p (r) Systolic BP (mmhg) Twenty-four hour (0.003) Daytime (0.026) Nighttime (-0.108) a Twenty-four hour within-subject SD (0.066) Daytime within-subject SD (-0.017) Nighttime within-subject SD (0.101) a Diastolic BP (mmhg) Twenty-four hour (0.097) Daytime (0.142) a Nighttime (-0.059) a Twenty-four hour within-subject SD (0.258) Daytime within-subject SD (0.029) Nighttime within-subject SD (0.029) a HR (BPM) Twenty-four hour (0.236) Daytime (0.239) Nighttime (0.190) a Twenty-four hour within-subject SD (0.182) Daytime within-subject SD (0.154) Nighttime within-subject SD (0.136) a hscrp, high-sensitivity C-reactive protein; SD, standard deviation; BP, blood pressure; HR, heart rate; BPM, beats per minute. a Spearman s correlation. (Table 4, Fig. 1). 나이, 성별, 체질량지수, 흡연력, 총콜레스테롤, 중성지방, 고밀도지단백등으로인한영향을보정하기위하여다중선형회귀분석을시행하였다 (Table 5). 다변량분석의결과로나이 (β = 0.213, p = 0.013) 와체질량지수 (β = 0.306, p = 0.001) 가 hscrp 와유의한관계가있음을확인하였으며 24시간활동성혈압을통하여얻어진혈압측정치중 24시간동안의이완기혈압의변동성만이 (β = 0.286, p = 0.011) hscrp 와연관성이있었다. 24시간활동성심장박동수및변동성과 hscrp 와의관계 24시간평균심장박동수는 75.0 ± 8.9회 / 분 (r = 0.236, p = 0.004), 활동시간동안의평균심장박동수는 77.7 ± 9.5회 / 분 (r = 0.239, p = 0.003), 수면시간동안의평균심장박동수는 64.5 ± 8.5회 / 분 (r = 0.190, p = 0.020) 이었으며이들모두 hscrp와양의상관관계를보였다. 또한 24시간평균심장박동수의표준편차는 10.9 ± 3.3회 / 분 (r = 0.182, p = 0.025) 으로 hscrp와양의상관관계를보였다 (Table 4, Fig. 2). 하지만다중선형회귀분석에서는활동시간동안의심장박동수 (β = 0.169, p = 0.049) 만 hscrp와유의한관계가있었다 (Table 5). 고찰혈압의변동성은일반인과고혈압환자에서표적장기손상및심혈관계합병증과연관이있다고알려졌으나 [3,5,6,16-19] 그 A B Figure 1. The relationships between 24-h diastolic blood pressure (DBP) (A) and 24-h DBP variability (B) with hscrp

5 - The Korean Journal of Medicine: Vol. 85, No. 1, A B C D Figure 2. The relationships between 24-h average HR (A), daytime average HR (B), 24-h HR variability (C) and nighttime average HR (D) with hscrp. 정확한기전은알려져있지않다. 염증반응은동맥경화의중요한병태생리학적요소로혈압의변동성이이와관련이있음이일부연구에서보고되어염증반응이혈압의변동성으로인한표적장기손상및심혈관계합병증에기여하였을것으로생각한다. Abramson 등 [9] 은고혈압이없는정상성인에서혈압의변동성이 CRP 및 tumor necrosing factor (TNF)-α와연관성이있음을보고하였으며 Tatasciore 등 [11] 은최근진단된 190명의고혈압환자에서활동시간동안의수축기혈압의변동성이 hscrp 및 soluble E-selectin과연관이있다고보고하였다. 하지만이들연구들은대부분서양인을대상으로시행한연구로모든 인종에일반화하여적용하기는어렵다. 실제로 Abramson 등의연구에서활동시간동안의이완기혈압의변동성과 TNFα는백인에서는연관성이없었으나흑인에서는연관성이있었으며통계적으로유의한수준은아니지만 CRP도비슷한경향을보여인종에따른혈압의변동성과염증반응에차이가있음을보여주었다 [9]. 국내에서시행된염증인자와혈압변동성과의관계에대한연구로는 Kim 등 [10] 이고혈압환자 52명을대상으로시행한연구가유일하다. 이연구에서 interleukin (IL)-6는활동시간동안의수축기혈압의변동성과관련이있었다. 또한 hscrp는혈압의일중변동과 (circardian variation) 연관성이있

6 - Dongmin Kim, et al. BP variability and HR to hscrp - Table 5. Multiple linear regression analysis of hscrp and related variables hscrp p (β) C.I. Age (0.213) Sex (0.052) BMI (0.306) Smoking (0.020) Serum creatinine (0.101) Total cholesterol (0.070) Triglycerides (0.036) HDL-C (-0.159) Twenty-four hour average systolic BP (-0.177) Twenty-four hour average diastolic BP (0.133) Twenty-four hour diastolic BP variability (0.286) Daytime average HR (0.169) Twenty-four hour HR variability (0.099) hscrp, high-sensitivity C-reactive protein; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; BP, blood pressure; HR, heart rate; β, multiple linear regression coefficient; C.I., confidence interval. r 2 = 었다. 하지만표준편차를이용한혈압의변동성과 hscrp와의연관성을밝히지는못하였으며다른염증인자로서 TNF-α 도혈압의변동성과는관련이없었다 [10]. 이와는다르게본연구에서는최근진단된고혈압환자에서 24시간동안의이완기혈압의변동성은 hscrp와유의한상관관계를보였다. 또한나이, 성별, 체질량지수, 혈중콜레스테롤, 평균혈압등을보정한후에도유의한결과를보였다. 이는저자들이확인한바로는한국인을대상으로한연구중유일한것이다. 그러나수축기혈압의변동성은이러한연관성을보이지않아이전의연구들과잘일치하는결과를확인하지는못하였다. 이러한경향은표적장기손상및심혈관계합병증과의연관성을관찰한연구에서도나타나며 [4,16,20] 인종, 혈압의정도등을비롯한대상환자의특징및연구방법의차이로인한것으로생각한다. 명확한규명을위하여향후더많은연구가필요할것이다. 24시간활동성혈압을통하여혈압, 혈압의변동성뿐만아니라심장박동수에대한정보도얻을수있으나이값의임상적의미에대해서는연구된바가거의없으며결과확인에있어간과되기쉬운지표이다. 반면안정시심장박동수는심혈관계합병증의위험인자로잘알려져있다 [12]. 또한심장박동수의변동성은 CRP 등염증인자와연관성이있다고알려져있다 [13-15]. 하지만이 들연구들은신체진찰시또는수초간의심전도검사시측정된심장박동수이거나생활심전도등을통하여측정된심장박동수의변동성으로 24시간활동성혈압을통하여얻은평균심장박동수또는심장박동수의변동성과의관계가규명된바는거의없다. 또한이러한지표를확대하여 24시간활동성혈압을통하여얻은심장박동수지표가심장혈관사건또는염증인자가연관되어있다고해석하는것은무리가있다. 본연구에서 24시간동안의평균심장박동수가높을수록 hscrp가높게나타났다. 이는생활심전도를통하여얻은평균심장박동수가높을수록, 또는 RR 간격이짧을수록염증인자인 CRP 혹은 IL-6 등이높다는기존의연구 [15] 와비슷한결과이다. 향후 24시간활동성혈압을통하여얻은평균심장박동수와심혈관계합병증과의관계와기존의심장박동수측정방법과의연관성을규명하는연구를진행한다면더많은정보를얻을수있을것으로기대한다. 결론적으로본연구를통하여최근진단된고혈압환자에서 24시간활동성혈압을통하여얻은 24시간동안의이완기혈압의변동성과평균심장박동수가 hscrp와연관성이있음을확인할수있었다. 이러한정보가고위험고혈압환자의선별및치료에도움이될수있을것으로기대된다. 본연구의제한점으로는단면적관찰연구로혈압변동성과

7 - 대한내과학회지 : 제 85 권제 1 호통권제 635 호 심장박동수등이 hscrp와의연관성이있다는것을알수있지만인과관계를규명할수없다는것이며이를위한종단적연구가필요하다. 또한비교적적은수의환자를대상으로시행한연구로다른환자군에적용하기어렵다는것등이제한점이될수있다. 요약목적 : 혈압의변동성과심장박동수는표적장기손상과심장혈관합병증과관련이있다. 하지만그정확한기전은밝혀져있지않다. 이에저자들은혈압의변동성및심장박동수와염증인자가관계가있는지확인하고자본연구를시행하였다. 방법 : 최근진단되거나새로이진단된 151명의고혈압환자의 24시간활동성혈압을분석하였다. 혈압의변동성은측정된혈압의표준편차로표시하였다. 24시간활동성혈압검사중동시에측정된평균심장박동수및표준편차를측정하였다. 혈중 high-sensitivity C-reactive protein (hscrp) 를염증인자로사용하였다. 결과 : 대상환자의평균나이는 44 ± 11.3세로이중남자는 74.2% 이었다. hscrp 는남자환자 (0.131 ± vs ± 0.023, p = 0.001) 및흡연력이있는환자 (0.136 ± vs ± 0.017, p = 0.003) 에서높게나타났다. 상관분석에서 24시간동안의이완기혈압의변동성은 hscrp와양의상관관계를보였다 (p = 0.002, r = 0.258). 또한 24시간동안 (p = 0.004, r = 0.236), 활동시간동안 (p = 0.003, r = 0.239), 수면시간동안의 (p = 0.020, r = 0.190) 평균심장박동수그리고 24시간동안의심장박동수의변동성은 (p = 0.025, r = 0.182) hscrp 와양의상관관계를보였다. 다중선형회귀분석에서 24시간동안의이완기혈압의변동성과 (β = 0.286, p = 0.011) 활동시간동안의평균심장박동수가 (β = 0.169, p = 0.049) hscrp 와유의한관계가있었다. 결론 : 24시간활동성혈압을통하여측정된이완기혈압의변동성및심장박동수는염증인자인 hscrp와연관성이있었다. 혈압의변동성과심장박동수는염증반응과연관하여심장혈관합병증에영향을주는것으로생각한다. 중심단어 : 혈압의변동성 ; 심장박동수 ; C 반응단백 ; 고혈압 감사의글 자료수집과정리에도움을주신강순옥, 남궁은지임상병리사에게감사를드립니다. REFERENCES 1. Mancia G, De Backer G, Dominiczak A, et al. ESH/ESC 2007 guidelines for the management of arterial hypertension. Rev Esp Cardiol 2007;60:968.e Hansen TW, Thijs L, Li Y, et al. Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations. Hypertension 2010; 55: Kikuya M, Hozawa A, Ohokubo T, et al. Prognostic significance of blood pressure and heart rate variabilities: the Ohasama Study. Hypertension 2000;36: Mancia G, Bombelli M, Facchetti R, 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: Tatasciore A, Renda G, Zimarino M, et al. Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects. Hypertension 2007;50: Verdecchia P, Angeli F, Gattobigio R, Rapicetta C, Reboldi G. Impact of blood pressure variability on cardiac and cerebrovascular complications in hypertension. Am J Hypertens 2007;20: Zakopoulos NA, Tsivgoulis G, Barlas G, et al. Time rate of blood pressure variation is associated with increased common carotid artery intima-media thickness. Hypertension 2005;45: Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5: Abramson JL, Lewis C, Murrah NV, Anderson GT, Vaccarino V. Relation of C-reactive protein and tumor necrosis factor-alpha to ambulatory blood pressure variability in healthy adults. Am J Cardiol 2006;98: Kim KI, Lee JH, Chang HJ, et al. Association between blood pressure variability and inflammatory marker in hypertensive patients. Circ J 2008;72: Tatasciore A, Zimarino M, Renda G, et al. Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension. Hypertens Res 2008;31:

8 - 김동민외 2 인. 혈압변동성및심장박동수와 hscrp Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50: Lampert R, Bremner JD, Su S, et al. Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men. Am Heart J 2008;156:759.e Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006; 97: Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 2004;25: Eto M, Toba K, Akishita M, et al. Impact of blood pressure variability on cardiovascular events in elderly patients with hypertension. Hypertens Res 2005;28: Pringle E, Phillips C, Thijs L, et al. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens 2003;21: Sander D, Kukla C, Klingelhöfer J, Winbeck K, Conrad B. Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: a 3-year follow-up study. Circulation 2000;102: Sega R, Corrao G, Bombelli M, et al. Blood pressure variability and organ damage in a general population: results from the PAMELA Study (Pressioni Arteriose Monitorate E Loro Associazioni). Hypertension 2002;39(2 Pt 2): Eguchi K, Ishikawa J, Hoshide S, et al. Night time blood pressure variability is a strong predictor for cardiovascular events in patients with type 2 diabetes. Am J Hypertens 2009;22:

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