Original Article Vol. 17, No. 4, December 2011 ISSN 2233-8136 http://dx.doi.org/10.5646/jksh.2011.17.4.177 Copyright c 2011. The Korean Society of Hypertension 고혈압환자에서혈압및고지혈증조절에의한경동맥내중막두께와좌심실심근량의변화 선병주, 강덕현, 박경민, 김용균, 황기원, 조성원, 김유리, 김대희, 송종민, 송재관 울산대학교의과대학서울아산병원심장내과 Changes in Carotid Intima-media Thickness and Left Ventricular Mass by Control of Blood Pressure and Hyperlipidemia in Hypertensive Patients Byung Joo Sun, MD, Duk-Hyun Kang, MD, Gyung-Min Park, MD, Yong-Giun Kim, MD, Ki Won Hwang, MD, Sung Won Cho, MD, Yoo Ri Kim, MD, Dae-Hee Kim, MD, Jong-Min Song, MD Jae-Kwan Song, MD Division of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ABSTRACT Background: Hypertensive patients often present with carotid atherosclerosis, and especially those with left ventricular hypertrophy (LVH) are known to have twice the prevalence of carotid atheroma. The aims of this study were to evaluate the changes in the severity of carotid atherosclerosis and left ventricular (LV) mass by control of blood pressure (BP) and hyperlipidemia in hypertensive patients. Methods: A total of 87 treated hypertensive patients who had been diagnosed as stage 2 hypertension on Joint National Committee 7 classification in past 1 year or LVH on electrocardiographic criteria were enrolled. Both at baseline and the end of study, repetitive measurements of carotid intima-media thickness (IMT) and LV mass indexed by body surface area were performed. Measurement of carotid IMT was conducted at bilateral sides of distal common carotid artery. Results: After the follow-up period of mean 16-months, there were significant lowering in systolic and diastolic BP, respectively (144.6 ± 19.2 to 131.3 ± 13.6 mm Hg, p < 0.001; 87.5 ± 11.3 to 79.6 ± 9.4 mm Hg, p < 0.001). Carotid IMT showed no significant change (0.75 ± 0.18 to 0.76 ± 0.18 mm, p = 0.310). Although there was significant reduction in LV mass index (107.9 ± 22.0 to 101.0 ± 18.4 g/m 2, p < 0.001), it was not correlated with the changes in carotid IMT (r = 0.141, p = 0.197). Conclusions: Anti-hypertensive therapy combined with statin if indicated did not show significant reduction in atherosclerotic burden of carotid artery, but it seemed to prevent further progression in hypertensive patients. Decrement in LV mass achieved by BP control was not correlated with changes in carotid IMT. (J Korean Soc Hypertens 2011;17(4):177-184) Key Words: Atherosclerosis; Left ventricular hypertrophy; Hypertension 논문접수일 : 2011.10.18, 수정완료일 : 2011.10.31, 게재승인일 : 2011.12.23 교신저자 : 강덕현주소 : 서울송파구풍납동 388-1 울산대학교의과대학서울아산병원심장내과 Tel: 02) 3010-3166, Fax: 02) 486-5918 E-mail: dhkang@amc.seoul.kr 서론 고혈압환자에서좌심실비대는관동맥질환, 급사, 심부전및뇌경색의독립적인위험인자로알려져있으며, 경 J Korean Soc Hypertens 2011;17(4):177-184 177
경동맥내중막두께와심근량의변화 증및중등도고혈압환자의 20 30%, 심한고혈압환자의 50 60% 에서심초음파상좌심실비대가동반된것으로보고되었다. 1-3) 한편경동맥의경화반은고혈압환자의 23% 에서관찰되며특히좌심실비대환자에서는유병률이 2배가까이높은것으로보고되었는데, 초음파를이용한경동맥내중막두께 (intima-media thickness) 의측정이매우간편하고재현성이높은진단방법으로이는심혈관질환의예후예측에유용한것으로보고되었다. 4-8) 적극적인고혈압조절로좌심실비대의호전을기대할수있음은잘알려져있으며, 경동맥동맥경화를표적으로한고용량스타틴 (hydroxymethylglutaryl coenzyme A reductase inhibitor) 요법의효과는몇몇연구에서보고되었다. 9-11) 그러나임상적측면에서각각의발현은독립적이지않으며, 현재까지고혈압이외의위험인자를동반하지않은저위험군에서고용량의스타틴요법은근거가미약하여, 고혈압과고지혈증등위험인자들의동시적인조절이경동맥동맥경화증의진행을막는보다효과적이고실제적인방법으로판단된다. 이에본연구에서는현재의치료가이드라인에준한혈압및고지혈증조절을시행한환자군에서경동맥초음파와심초음파를이용하여경동맥내중막두께및좌심실심근량지수 (left ventricular mass index) 의변화를측정함으로써경동맥동맥경화및좌심실비대의개선효과를평가하고자하였다. 대상및방법 1. 연구대상서울아산병원외래에서투약중인기존의고혈압환자중 2008년 2월이후대상자를선별하여최근 1년이내외래에서측정된혈압이 Joint National Committee 7 (JNC 7) 분류상 2기에해당하였거나심전도기준상좌심실비대를보이는, 스타틴처방력이없는연속적인환자를포함하였다. 12,13) 제외기준은병원측정혈압 > 180/110 mm Hg, 이차성고혈압, 심근경색의과거병력이나관동맥조영술에서확인된관동맥질환, 임상적으로말초혈관질환이의심되거나 ankle brachial pressure index < 0.9인경 우, 울혈성심부전, 뇌경색의병력, 신기능의감소 ( 혈청크레아티닌 >1.5mg/dL), 심방세동, 임산부나수유부그리고안지오텐신전환효소차단제 ( 또는안지오텐신수용체차단제 ) 및스타틴에금기증이있는경우로하였다. 연구에포함된모든환자로부터서면동의서를구득하였고, 연구절차및모든검사는본병원의임상연구관리위원회 (Institutional Review Board) 허가후에이루어졌다. 2. 연구설계혈압측정은담당의사에의해시행되었고, 수은혈압계로 2회측정한값의평균을취하였다. 적절한혈압조절목표는 JNC 7에근거하여, 140/90 mm Hg 이하또는당뇨에서 130/80 mm Hg 이하로정의하였으며, 혈압조절양상에따라담당의사의판단으로약제를조절하여 3개월또는 6개월후에추적관찰하였다. 13) 혈청지질검사는 9개월간격으로시행되었으며, 약제선택및투여는 National Cholesterol Education Program의 Adult Treatment Panel III (NCEP-ATP III) 에근거하였다. 14) 모든환자에서연구시작과종료시점에경동맥초음파와심초음파를반복시행하였고, 이를통하여연구의일차목적인경동맥내중막두께의변화를측정하고이차목적으로좌심실심근량지수의변화및경동맥내중막두께와의연관성을분석하고자하였다. 객관적으로치료효과를평가하기위하여검사자가임상자료를알수없도록하였고, 추후영상의분석에서도치료전후를알수없도록저장된초음파영상을무작위순서로제시하였다. 경동맥내중막두께의측정법은미국심초음파학회가이드라인에근거하였다. 15) 모든환자에서 ie33 (Philips Medical Systems, Andover, MA, USA) 의 12 MHz 선형탐촉자를이용하여좌우총경동맥원위부의 B모드초음파영상을얻었고영상의분석은 QLAB (Philips Medical Systems) software를이용하였으며, 탐촉자원위벽의 1 cm 분절에서평균내중막두께를측정하여좌우양측의평균값을취하였다. 9) 좌심실심근량지수는미국심초음파학회가이드라인에따라산출하였고남자에서 116 g/m 2, 여자에서 104 g/m 2 보다큰경우좌심실비대로정의하였다. 16) 178 The Korean Society of Hypertension
선병주, 강덕현, 박경민, 김용균, 황기원, 조성원 et al. Table 1. Baseline characteristics of patients All patients (n=87) Age (yr) 55.9 ± 10.0 Male sex 63 (72.4) Diabetes 3 (3.4) Current smoker 9 (10.3) Serum creatinine (mg/dl) 0.9 ± 0.2 Body mass index (kg/m 2 ) 25.8 ±2.6 Blood pressure (mm Hg) SBP 144.6 ± 19.2 DBP 87.5 ± 11.3 Anti-hypertensive medications ACEi/ARB 80 (92.0) Beta blocker 15 (17.2) Calcium channel blocker 73 (83.9) Diuretics 32 (36.8) Monotherapy 13 (14.9) Combination therapy 74 (85.1) Lipid profile (mg/dl) Total cholesterol 187.7 ± 28.4 LDL cholesterol 116.5 ± 26.1 HDL cholesterol 51.6 ± 12.6 Triglyceride 161.5 ± 104.1 Left ventricular ejection fraction (%) 62.1 ± 3.5 Left ventricular mass index (g/m 2 ) 107.9 ± 22.0 Male 110.4 ± 22.7 Female 99.2 ± 17.8 Mean carotid IMT, both sides (mm) 0.75 ± 0.18 Right side (mm) 0.74 ± 0.19 Left side (mm) 0.75 ± 0.18 Values are presented as mean ± standard deviation or number (%). SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; LDL, low-density lipoprotein; HDL, high-density lipoprotein; IMT, intima-media thickness. 3. 통계분석 The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) 및 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 연구결과에근거하여, 1년 6개 월간의적절한혈압조절및스타틴요법이병행될때총경동맥내중막두께에 0.005 ± 0.010 mm의감소가예측되었고 α 오차 = 0.05, β 오차 =0.2로피험자수는 80명으로추정되었다. 9,17) 모든연속변수는평균 ± 표준편차로표시하고각각의변화량은추적치에서기저치를제한값으로정의하였으며, 비교를위하여대응표본 t 검정을시행하였다. 이분변수에는카이제곱또는 Fisher의정확한검정을적용하였다. 모든경우에 p값이 0.05 이하일때통계적으로유의한것으로판단하였고, 통계분석은 SPSS ver. 15.0 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 결과 2008년 2월부터 2009년 12월까지외래환자중연구기준에합당한 101명을선별하여이중관동맥질환 4명, 심방세동 1명, 이차성고혈압 1명, 연구참여의사가없는 8명을제외한 87명 ( 남자 63명, 평균 55.9 ± 10.0세 ) 이연구에포함되었다 (Table 1). 연구시작시점에서평균혈압은 144.6 ± 19.2 mm Hg/87.5 ± 11.3 mm Hg으로 74명 (85%) 이두가지이상의항고혈압약제를병합하여사용중이었으며, 이중안지오텐신전환효소차단제 / 안지오텐신수용체차단제 (80명, 92%) 와칼슘수용체차단제 (73명, 84%) 의사용비율이높았다. 혈청총콜레스테롤 (total cholesterol) 및저밀도지단백콜레스테롤 (low density lipoprotein [LDL] cholesterol) 은각각 187.7 ± 28.4 mg/dl, 116.5 ± 26.1 mg/dl 이었고전체 87명의환자중당뇨가있는 3명을포함하여 75 (86%) 명의환자가 2개이상의심혈관질환주위험인자를동반하였다. 14) 경동맥초음파상좌우총경동맥내중막두께의평균은 0.75 ± 0.18 mm이었으며, 심초음파상좌심실구혈률은 62.1 ± 3.5%, 좌심실심근량지수는남녀각각에서 110.4 ± 22.7 g/m 2, 99.2 ± 17.8 g/m 2 으로남자 25명 (40%), 여자 5명 (21%) 이좌심실비대를보였다. 전체 87명 (100%) 에서평균 16개월경과후심초음파와경동맥초음파추적검사가시행되었다. 1. 혈압과고지혈증의조절연구기간동안 78명 (90%) 의환자에서두가지이상의항고혈압약제가병합되어사용되었고, 연구종료시점에서의 J Korean Soc Hypertens 2011;17(4):177-184 179
경동맥내중막두께와심근량의변화 Table 2. Changes in blood pressure, lipid profile, left ventricular mass index and carotid IMT after follow-up Blood pressure (mm Hg) Base (n = 87) Follow-up (n = 87) p-value SBP 144.6 ± 19.2 131.3 ± 13.6 <0.001 DBP 87.5 ± 11.3 79.6 ± 9.4 <0.001 Lipid profile (mg/dl) Total cholesterol 187.7 ± 28.4 172.4 ± 25.4 <0.001 LDL cholesterol 116.5 ± 26.1 98.7 ± 20.5 <0.001 HDL cholesterol 51.6 ± 12.6 49.8 ± 12.9 0.183 Triglyceride 161.5 ± 104.1 162.6 ± 95.4 0.775 Left ventricular mass index (g/m 2 ) 107.9 ± 22.0 101.0 ± 18.4 <0.001 Male 110.4 ± 22.7 104.3 ± 18.2 <0.001 Female 99.2 ± 17.8 92.1 ± 16.4 0.005 Mean carotid IMT, both sides (mm) 0.75 ± 0.18 0.76 ± 0.18 0.310 Right side (mm) 0.74 ± 0.19 0.73 ± 0.18 0.405 Left side (mm) 0.75 ± 0.18 0.76 ± 0.18 0.795 Values are presented as mean ± standard deviation. SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; IMT, intima-media thickness. 혈압은기저치에비하여수축기, 이완기모두유의한감소를보였다 (Table 2). 연구중간방문시의혈압을반영한평균치는 138.1 ± 13.2 mm Hg/83.1 ± 7.1 mm Hg이었으며, 이를 JNC 7에근거한혈압목표치와비교하였을때 55명 (63%) 이연구기간동안적절한혈압조절을유지한것으로나타났다. 13) 혈압약제의단독요법군과병합요법군사이에혈압변화폭과혈압목표치달성비율의차이는없었으며, 또한이에대한약제간의차이도관찰되지않았다. 고지혈증의조절을위해총 36명에서스타틴제제가처방되었고 ( 고위험군, LDL cholesterol > 100 mg/dl 2명 ; 중등고위험군, LDL cholesterol > 130 mg/dl 24명 ; 중등도위험군, LDL cholesterol > 160 mg/dl 6명 ; 저위험군, LDL cholesterol > 160 mg/dl 4명 ) 20명에서는치료적생활습관교정이시행되어, 14) 추적검사결과 total cholesterol 및 LDL cholesterol 은유의한감소를보였다 (Table 2). 2. 경동맥초음파및심초음파 (Table 2) 총경동맥내중막두께는연구기간전후유의한변화를 보이지않았으며 (0.75 ± 0.18 mm vs. 0.76 ± 0.18 mm, p = 0.310), 좌심실심근량지수의변화량과상관관계를보이지않았다 (r = 0.141, p = 0.197) (Fig. 1A). 연구종료시점에서측정된좌심실심근량지수는연구시작시점에비하여유의한감소를보였고 (107.9 ± 22.0 g/m 2 vs. 101.0 ± 18.4 g/m 2, p < 0.001), 좌심실심근량지수의변화량과기저치사이에유의한상관관계가관찰되었다 (r = -0.547, p < 0.001) (Fig. 1B). 반면좌심실심근량지수의변화량은연구전후혈압측정치, 혈압변화량등과상관관계를보이지않았고, 혈압약제의병합요법여부, 약제종류사이에유의한차이를보이지않았다. 고찰본연구에서혈압조절을위주로하고 NCEP-ATP III 기준에의해필요시통상적인용량의스타틴을병용했던환자군은 16개월간격의초음파추적검사상총경동맥내중막두께의유의한변화를보이지않았다. 14) Roman 등 4) 180 The Korean Society of Hypertension
선병주, 강덕현, 박경민, 김용균, 황기원, 조성원 et al. 의연구에서고혈압환자의좌심실심근량과경동맥상죽상경화반유병률사이의연관성이보고되었고, Jikei Heart Study 결과고혈압약제인안지오텐신수용체차단제가뇌경색의발생을유의하게감소시키는것으로보고되 수가 107.9 ± 22.0 g/m 2 로좌심실비대는 30명 (34%) 에서만관찰되었으나, 평균 16개월간의혈압조절후유의한좌심실심근량지수의감소를나타냈다. 혈압조절로인한좌심실심근량의감소를기술하였던 Losartan Intervention 어, 18) 혈압조절이경동맥동맥경화증에미치는효과가 For Endpoint Reduction (LIFE) 연구에서혈압의기저치 임상적으로중요함을시사하였다. 본연구에서경동맥내중막두께의의미있는변화를관찰하지못했던반면 ARBITER 연구에서는 atorvastatin 80 mg을 1년간사용하여의미있는호전을보였고, Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) 연구에서도 rosuvastatin 40 mg을사용한군이위약군에비하여유의한동맥경과진행의억제효과를보여공통적으로가해진고용량의스타틴요법이효과적이었음을시사한다. 9,11) 이에비하여본연구에서스타틴의사용빈도는 36명 (41%) 에그치고또한통상적인용량으로스타틴에의한직접적인효과는미약하였고, 혈압조절병행으로기대되었던상승효과도기존연구에서관찰된고용량스타틴요법의동맥경화억제효과에는미치지못했던것으로보인다. 다만, METEOR 연구에서위약군이의미있는경동맥내중막두께의증가를보였던점에비추어본연구에서는혈압조절이동맥경화의진행을억제하는요인으로작용했을것으로이해된다. 11) 본연구의대상환자들은혈압상승폭이작으며 (144.6 ± 19.2 mm Hg/87.5 ± 11.3 mm Hg) 평균좌심실심근량지 가 173±20mmHg/95±11mmHg이며평균좌심실심근량지수 123 ± 26 g/m 2 로 75% 의환자에서좌심실비대를동반하였다는것과비교할때, 10) 본연구는평균적으로좌심실심근량의증가가크지않은환자군에서도혈압조절에의한표적장기보호효과가유효함을보였다. Framingham 연구에서심초음파로측정된좌심실심근량지수가 50 g/m 2 증가할때마다심혈관합병증발생의위험도가 50% 증가하였고, 좌심실비대의일차적자극요인은수축기혈압으로일생동안누적되는혈압의부하를고려한다면고혈압환자에서적극적인혈압조절로얻는치료효과는장기적예후향상측면에서유리하게작용할것으로예측된다. 19) 본연구에서는좌심실심근량지수의감소와경동맥내중막두께사이에서유의한관계를발견하지못하였다. 고혈압치료에의한좌심실비대의호전은과거의연구들에서인과관계가기술되었으나, 경동맥의동맥경화에대한치료는고용량스타틴요법의효과에도연구들간의차이점이있고, amlodipine을사용한 The Prospective Randomized Evaluation of the Vascular Effects of Fig. 1. Correlation of change* in LV mass index with change in carotid IMT (A), with baseline LV mass index (B). LV, left ventricle; IMT, intima-media thickness; BSA, body surface area. * Value of follow-up minus baseline. J Korean Soc Hypertens 2011;17(4):177-184 181
경동맥내중막두께와심근량의변화 Norvasc Trial (PREVENT), niacin을병합사용한 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 HDL and LDL Treatment Strategies (ARBITER 6-HALTS) 등여러치료표적과접근법들이혼재하여, 기존연구결과들을바탕으로좌심실비대와의연관성을찾기란어려운실정이다. 6,9-11,17,20,21) 따라서향후에는엄격한혈압조절과고용량의스타틴요법이결합된연구를통해두질환의치료반응간의연관성을찾을수있을것으로보인다. 본연구는단일기관에서시행되어환자군의선정에서선택오차 (selection bias) 를배제하지못하였고, 위약군없이단일군만을대상으로하여질환의자연적진행형태와비교하지못하였다. 또한대상군을 JNC 7 분류상 2기또는심전도기준상좌심실비대로하여동질성에제약이있었으며, 이는선별대상을투약중인환자들로하였으므로좌심실비대를동반한경우이미혈압이조절된상태라하더라도이전에있었던장기간의혈역학적부담을반영한다고해석하였기때문이다. 혈압약제는주로안지오텐신전환효소차단제 / 안지오텐신수용체차단제가대부분의환자 (80명, 92%) 에서사용되어, 약제의종류에따른좌심실심근량지수및경동맥내중막두께에대한효과를평가할수없었다. 또한관동맥질환등고위험군환자들이배제되어실제적인스타틴사용빈도가낮았으므로고지혈증과혈압조절의상승효과를평가하는데한계가있었다. 결론적으로혈압조절에더해 NCEP-ATP III 기준에의해고지혈증을조절함으로써 16개월간격의초음파추적검사상좌심실심근량의감소를유발하고, 총경동맥내중막두께의진행을예방할수있었다. 좌심실심근량의감소는경동맥내중막두께의변화와연관성을보이지는않았으며, 연관성을찾기위하여는향후혈압조절과고용량의스타틴요법이병합된연구가필요할것으로생각된다. 요약연구배경 : 경동맥의동맥경화는고혈압환자에동반되 며, 특히좌심실비대환자에서는경동맥경화반의유병률이 2배가까이높다고알려졌다. 본연구에서는혈압조절을위주로현재의치료가이드라인에준해고지혈증을병합치료하였던환자군에서경동맥동맥경화및좌심실비대의개선효과를평가하고자하였다. 방법 : 치료중인고혈압환자중최근 1년이내에 Joint National Committee 7 분류상 2기에해당하였거나심전도기준상좌심실비대를보이는환자 87명을대상으로하였다. 모든환자에서연구시작과종료시점에경동맥초음파와심초음파를반복시행하였으며, 경동맥내중막두께는좌우총경동맥원위벽의 1cm 분절에서얻은평균값을취하였고, 좌심실심근량지수는미국심초음파학회가이드라인에따라산출하였다. 결과 : 전체 87명중 78명 (90%) 의환자에서두가지이상의제재가병합되어사용되었고, 혈압약제의단독요법군과병합요법군사이및약제종류사이에혈압강하효과는차이가없었다. 연구기간전후혈압은수축기 (144.6 ± 19.2 mm Hg vs. 131.3 ± 13.6 mm Hg, p < 0.001), 이완기 (87.5 ± 11.3 mm Hg vs. 79.6 ± 9.4 mm Hg, p < 0.001) 모두유의한감소를보였다. 평균 16개월후의추적검사에서좌우총경동맥내중막두께는유의한변화를보이지않았다 (0.75 ± 0.18 mm vs. 0.76 ± 0.18 mm, p = 0.310). 좌심실심근량지수는유의한감소를보였고 (107.9 ± 22.0 g/m 2 vs. 101.0 ± 18.4 g/m 2, p < 0.001), 총경동맥내중막두께의변화량과상관관계를보이지않았다 (r = 0.141, p = 0.197). 결론 : 고혈압환자에서혈압조절에더한현재의가이드라인에준한고지혈증조절은 16개월간격의초음파추적검사상좌심실심근량의감소를유발하고, 총경동맥내중막두께의증가를예방할수있었다. 좌심실심근량의감소는경동맥내중막두께의변화와연관성을보이지는않았다. References 1. Cuspidi C, Negri F, Muiesan ML, Capra A, Lonati L, Milan A, et al. Prevalence and severity of echocardiographic left ventricular hypertrophy in hypertensive patients in clinical 182 The Korean Society of Hypertension
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