李春輝，孟威宏

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低舒張壓的單純收縮期高血壓研究新進(jìn)展

李春輝，孟威宏*

（沈陽(yáng)軍區(qū)總醫(yī)院干部病房一科，沈陽(yáng) 110016）

在有些高齡患者中，會(huì)出現(xiàn)舒張壓（DBP）＜60mmHg高血壓患者，即低DBP的單純收縮期高血壓（ISH）。越來越多的證據(jù)表明DBP＜70mmHg對(duì)機(jī)體是不利的，而低DBP的ISH患者常具有更多的心血管危險(xiǎn)因素和更多的心血管事件風(fēng)險(xiǎn)，成為老年高血壓降壓治療的難點(diǎn)，使用硝酸酯類藥物進(jìn)行治療可能是一個(gè)有益的選擇。

低舒張壓；高血壓；老年人；J形曲線

單純收縮期高血壓（isolated systolic hypertension，ISH）是老年高血壓的最常見類型，＞70歲的高血壓人群中ISH患病率＞90%[1]，在高齡老年高血壓患者中甚至?xí)霈F(xiàn)舒張壓（diastolic blood pressure，DBP）＜60mmHg（1mmHg＝0.133kpa）的ISH。我們對(duì)這種特殊類型的高血壓往往認(rèn)識(shí)不足，本文擬對(duì)近年來這種特殊類型的高血壓的新進(jìn)展做一綜述。

1 低DBP的產(chǎn)生機(jī)制及病理生理意義

血壓的變化與年齡存在一定相關(guān)性，一般在50～60歲以后，DBP開始呈現(xiàn)下降趨勢(shì)[2,3]，收縮壓（systolic blood pressure，SBP）繼續(xù)隨著年齡的增大而升高，脈壓逐漸增大，所以老年高血壓以ISH為常見，由于常常合并主動(dòng)脈關(guān)閉不全，血壓測(cè)量時(shí)大多采用柯氏音的第Ⅴ時(shí)相記錄DBP。其DBP低的原因與動(dòng)脈硬化彈性降低及心室舒張期、血管收縮功能下降等因素有關(guān)。老年人由于大動(dòng)脈的硬化以及大血管彈力纖維被膠原纖維取代，使大血管彈性回縮力下降，同時(shí)小動(dòng)脈血管阻力沒有相應(yīng)地增加[4]，在心臟收縮時(shí)血管彈性擴(kuò)張不足，使血管內(nèi)壓力迅速上升，表現(xiàn)為較高的SBP；而在心臟舒張期，由于大動(dòng)脈與小動(dòng)脈之間壓力差的增大，使血液迅速流入小動(dòng)脈，血管內(nèi)壓力快速下降，表現(xiàn)為較低的DBP。Mancusi等[5]發(fā)現(xiàn)，ISH患者左室心肌質(zhì)量明顯高于其他類型高血壓患者，提示心肌重構(gòu)也參與了這一過程的變化。而Franklin等[6]發(fā)現(xiàn)DBP＜70mmHg的ISH患者年齡更高，且糖尿病和冠心病患病率是70mmHg≤DBP＜90mmHg患者的2倍。上述情況說明年齡越高，DBP越低，脈壓差越大，動(dòng)脈硬化越重，更易發(fā)生心血管事件。

DBP降低可對(duì)機(jī)體產(chǎn)生相應(yīng)危害，心臟收縮期冠狀動(dòng)脈血流量只有舒張期的20%～30%，DBP決定了冠脈的血流灌注，過低的DBP可能導(dǎo)致冠脈灌注不足。Franklin等[7]通過對(duì)1 924名年齡在50～79歲的無冠心病的高血壓患者平均隨訪14.3年，發(fā)現(xiàn)＞60歲的高血壓患者DBP與冠心病的發(fā)病呈負(fù)相關(guān)。Fujishima等[8]觀察無陳舊性心肌梗死的老年高血壓患者發(fā)現(xiàn)DBP低于74.5mmHg是心電圖呈現(xiàn)心肌缺血樣改變的獨(dú)立預(yù)測(cè)因子。Lagro等[9]還發(fā)現(xiàn)，老年高血壓患者當(dāng)出現(xiàn)低DBP的時(shí)候，23個(gè)月內(nèi)死亡風(fēng)險(xiǎn)高達(dá)19%。Ungar等[10]發(fā)現(xiàn)脈壓為78mmHg的ISH患者其死亡風(fēng)險(xiǎn)是平均脈壓差為46mmHg組患者的5倍。而低DBP的ISH高血壓患者脈壓差將＞90mmHg，其心腦血管事件和死亡風(fēng)險(xiǎn)將更高。因此，低的DBP不僅增加冠脈事件的風(fēng)險(xiǎn)，還與死亡風(fēng)險(xiǎn)的增加有關(guān)。

2 ISH患者降壓治療DBP最低耐受值的界定

研究者們對(duì)于降壓治療的J型曲線已爭(zhēng)論了30多年，最早認(rèn)為J點(diǎn)應(yīng)＞90mmHg，這一觀點(diǎn)是1979年由Stewart等[11]提出的，通過對(duì)無并發(fā)癥的原發(fā)性高血壓患者隨訪6.5年發(fā)現(xiàn)，DBP＜90mmHg與DBP在100～109mmHg相比，前者心肌梗死的風(fēng)險(xiǎn)增加了5倍。但后來的一些臨床研究提示，最佳的DBP值應(yīng)在80～90mmHg之間。1988年，Cruickshank[12]通過對(duì)6個(gè)臨床試驗(yàn)共14 536名高血壓患者的數(shù)據(jù)分析發(fā)現(xiàn)，對(duì)于有冠心病和周圍動(dòng)脈疾病的患者DBP J點(diǎn)是85mmHg。普伐他汀或阿托伐他汀評(píng)估和感染治療?心肌梗死溶栓（PROVE IT-TIMI）22[13]研究數(shù)據(jù)也顯示，對(duì)于心肌梗死患者，最佳DBP為80～90mmHg。國(guó)際緩釋維拉帕米?群多普利研究[14]（International Verapamil SR-Trandolapril Study，INVEST）表明DBP J點(diǎn)在84mmHg。若DBP達(dá)到此點(diǎn)后進(jìn)一步降低，則致死或非致死性心腦血管事件發(fā)生率增加。當(dāng)DBP降至70～60mmHg時(shí)，主要終點(diǎn)發(fā)生率增高了近1倍；當(dāng)DBP＜60mmHg時(shí)，主要終點(diǎn)發(fā)生率增高了2倍。Dorresteijn等[15]的研究也證明，有血管疾病的患者，最佳DBP為82mmHg，過低或過高都會(huì)導(dǎo)致心血管疾病及全因死亡率的增加。HOT研究[16]將DBP降至82.6mmHg，沒有出現(xiàn)J形曲線。但近年來較多的證據(jù)表明，人體所能耐受的DBP應(yīng)約在70mmHg。Arima等[17]通過對(duì)預(yù)防卒中復(fù)發(fā)（PROGRESS）研究數(shù)據(jù)分析發(fā)現(xiàn)，將DBP降至72mmHg時(shí)仍是安全的。日本一項(xiàng)針對(duì)＞80歲的高齡老年高血壓患者的隨訪發(fā)現(xiàn)[18]，DBP＜70mmHg死亡風(fēng)險(xiǎn)明顯增高（RR值2.47）。Tringali等[19]對(duì)14270名高血壓患者進(jìn)行了為期2年的橫斷面調(diào)查，結(jié)果表明，DBP＜70mmHg與高血壓患者的全因死亡風(fēng)險(xiǎn)增加有關(guān)。而Framingham心臟研究（FHS）[20]最新數(shù)據(jù)也表明，DBP＜70mmHg的ISH患者，與DBP在70～89mmHg的ISH患者相比，不僅冠狀動(dòng)脈風(fēng)險(xiǎn)增加，心力衰竭和缺血性卒中的風(fēng)險(xiǎn)也明顯增加。不同的臨床研究得出的最低DBP值存在很大的差異，INVEST研究[21,22]給我們新的提示，不同年齡，不同血運(yùn)重建方式對(duì)DBP的耐受是不一樣的，冠狀動(dòng)脈旁路移植術(shù)術(shù)后低DBP耐受值高于經(jīng)皮冠狀動(dòng)脈介入治療術(shù)后患者。這就提示我們患者對(duì)低灌注的耐受情況是受多方面因素影響的，不僅與DBP值有關(guān)，還可能與血液黏滯度、血小板黏附聚集能力、是否應(yīng)用他汀類藥及血管自身狹窄情況等多種因素有關(guān)。不同患者所能耐受DBP的最低值是不同的，但目前多數(shù)證據(jù)顯示，ISH患者DBP＜70mmHg對(duì)機(jī)體是不利的。

3 老年ISH患者如何從降壓治療中獲益

早期研究認(rèn)為，人體理想血壓為115/75mmHg[23]，血壓每增加20/10mmHg，心血管死亡風(fēng)險(xiǎn)增加1倍。長(zhǎng)期有效地控制血壓可使心腦血管病發(fā)病率和死亡率大幅度下降。但新近臨床研究顯示，很少能直接將患者血壓降至理想血壓水平，老年高血壓患者降壓目標(biāo)值為150/90mmHg[24?26]，而這一目標(biāo)值對(duì)ISH患者的降壓治療缺乏指導(dǎo)意義。

目前已經(jīng)完成的有關(guān)老年高血壓降壓治療的大型臨床試驗(yàn)有9項(xiàng)（表1），其中老年人收縮期高血壓項(xiàng)目（Systolic Hypertension in the Elderly Program，SHEP）、歐洲收縮期高血壓臨床試驗(yàn)（Systolic Hypertension-Europe，Syst-Eur）和中國(guó)收縮期高血壓臨床試驗(yàn)（Systolic Hypertension in China，Syst-China）等3項(xiàng)研究是專門針對(duì)ISH。Syst-Eur和Syst-China兩項(xiàng)研究終點(diǎn)血壓分別為152/79mmHg和150/81mmHg，試驗(yàn)結(jié)果表明，無論是在心腦血管事件還是全因死亡率上，患者都是獲益的。SHEP研究入組患者平均DBP為75mmHg，治療組終點(diǎn)DBP為68mmHg，對(duì)照組為73mmHg。治療組在腦卒中發(fā)病率明顯降低，但在心肌梗死和全因死亡率方面并沒有明顯獲益。提示隨著DBP的進(jìn)一步下降，患者凈獲益在降低。目前還沒有將ISH患者DBP降至＜68mmHg獲益的循證醫(yī)學(xué)證據(jù)，因此就現(xiàn)有的循證醫(yī)學(xué)證據(jù)而言，68～70mmHg應(yīng)為ISH降壓治療的極限，更低的DBP能否從降壓治療中獲益尚不確定。

4 老年低DBP的ISH治療探討

如何處理低DBP的ISH患者是一個(gè)非常棘手的問題。雖然指南指出老年人降壓至150/90mmHg這一目標(biāo)值，但因其沒有體現(xiàn)出不同類型高血壓在降壓治療方面的差異性，無法成為低DBP的ISH參照標(biāo)準(zhǔn)。對(duì)于DBP＜68mmHg甚至＜60mmHg的ISH的降壓治療尚無循證醫(yī)學(xué)證據(jù)可循。2011年美國(guó)老年高血壓專家共識(shí)[27]建議要盡量避免DBP＜65mmHg的情況出現(xiàn)。盡管低DBP可能導(dǎo)致心肌灌注不足，但如果患者SBP過高仍可能導(dǎo)致心腦血管事件的發(fā)生，也就是說SBP高危害更大，應(yīng)盡量把SBP降低到＜140mmHg（＜80歲）或＜150mmHg（＞80歲），如果血管狹窄嚴(yán)重，有缺血癥狀，應(yīng)進(jìn)行血管重建術(shù)，故SBP的升高程度是選擇用藥的基本標(biāo)準(zhǔn)。一些經(jīng)驗(yàn)性的治療提出[26]，當(dāng)DBP＜60mmHg時(shí)，如SBP＜150mmHg，不宜降壓治療；如SBP 150～179mmHg，可謹(jǐn)慎給予小劑量降壓藥；如SBP≥180mmHg，應(yīng)給予小劑量降壓藥治療。具體到患者時(shí)還應(yīng)結(jié)合其年齡、臨床癥狀、體征、血管狹窄程度及靶器官損害情況等綜合判定，進(jìn)行個(gè)體化用藥。

表1 老年高血壓的臨床試驗(yàn)

EWPHE: European Working Party on High Blood Pressure in the Elderly; SHEP: Systolic Hypertension in the Elderly Program; STOP-H: Swedish Trial in Old Patients with Hypertension; MRC-elderly: Medical Research Council Trial of Treatment of Hypertension in Older Adults; Syst-Eur: Systolic Hypertension-Europe; Syst-China: Systolic Hypertension in China; SCOPE: The Study on Cognition and Prognosis in the Elderly; HYVET: Hypertension in the Very Elderly Trial; JATOS: Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; BP: blood pressure; SBP: systolic blood pressure. 1mmHg＝0.133kPa

當(dāng)需要降壓治療時(shí)，選取哪種藥物也是值得探討的問題。由于ISH與動(dòng)脈硬化明顯相關(guān)，因此理論上具有抗動(dòng)脈硬化的藥物如血管緊張素轉(zhuǎn)換酶抑制劑（angiotensin-converting enzyme inhibitor，ACEI）、血管緊張素受體拮抗劑（angiotensin receptor blockers，ARB）、鈣通道阻滯劑（calcium channel blocker，CCB）等[28]都適用于老年ISH的治療。SHEP、Syst-Eur、Syst-China 3個(gè)ISH的臨床試驗(yàn)證明，噻嗪類利尿劑（thiazine diuretics）或二氫吡啶類CCB可減少患者心、腦血管病的復(fù)合終點(diǎn)，尤其是顯著減少腦卒中發(fā)生率，為ISH患者降壓治療提供了有效性和安全性證據(jù)。氯沙坦治療伴有左室肥厚的ISH患者的心血管事件發(fā)生率和死亡率[29][氯沙坦干預(yù)終點(diǎn)縮?。↙osartan Intervention for Endpoint Reduction，LIFE）-ISH研究]的結(jié)果表明，在血壓下降幅度相似的情況下，氯沙坦組的主要復(fù)合終點(diǎn)事件更低，且減少了新發(fā)糖尿病風(fēng)險(xiǎn)，降低了心血管死亡、全因死亡以及腦卒中的風(fēng)險(xiǎn)。LIFE-ISH研究提示，ARB類藥物成為繼利尿劑和CCB之后又一個(gè)有循證醫(yī)學(xué)證據(jù)的治療ISH的藥物。但這些藥物在降低SBP的同時(shí)也不同程度地降低了DBP，這對(duì)于低DBP的ISH患者來說就會(huì)存在降低冠脈灌注增加心血管事件的風(fēng)險(xiǎn)。

從理論上講，適用于低DBP的ISH藥物應(yīng)最大限度地降低SBP，同時(shí)最低限度減少冠狀動(dòng)脈灌注。硝酸酯類藥物通過釋放一氧化氮改善大動(dòng)脈順應(yīng)性，其對(duì)動(dòng)脈的擴(kuò)張主要體現(xiàn)在對(duì)大動(dòng)脈而非終末阻力動(dòng)脈血管。通過擴(kuò)張大動(dòng)脈的直徑、增強(qiáng)動(dòng)脈壁的舒張功能和改善動(dòng)脈順應(yīng)性，從而達(dá)到降低SBP的目的，而此方法對(duì)DBP的影響非常有限；由于它具有擴(kuò)張冠狀動(dòng)脈的作用，因此不會(huì)降低冠狀動(dòng)脈血流灌注。一些小型的臨床觀察[30?32]，已顯示出其在治療ISH方面的可行性，前景看好，但尚缺乏大型臨床試驗(yàn)的證據(jù)。

總之，低DBP的ISH是老年高血壓處理的難點(diǎn)，要重視DBP過低所帶來的潛在風(fēng)險(xiǎn)，尤其對(duì)于高齡老人，必須平衡其獲益和風(fēng)險(xiǎn)，在充分遵循循證醫(yī)學(xué)證據(jù)的前提下，做到選藥個(gè)體化，盡量選擇對(duì)DBP和冠狀動(dòng)脈灌注影響小的藥物。隨著經(jīng)驗(yàn)的積累和不斷地探索總結(jié)，優(yōu)化針對(duì)這一特殊類型的高血壓的治療方法，必將進(jìn)一步改善老年高血壓患者的預(yù)后。

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（編輯: 李菁竹）

New research progress in isolated systolic hypertension with low diastolic pressure

LI Chun-Hui, MENG Wei-Hong*

(First Department of Cadre’s Wards, General Hospital of Shenyang Military Command, Shenyang 110016, China)

Some elderly hypertensive patients may manifest as diastolic blood pressure (DBP) lower than 60mmHg, a phenomenon known as isolated systolic hypertension (ISH) with low diastolic pressure. More and more evidence shows that DBP ＜70mmHg is detrimental to the body. What’s more, the ISH patients with lower DBP often have more risk factors and are of higher risk for cardiovascular events, which become a difficulty for the treatment of the elderly hypertension. Nitrates may be a good option.

low diastolic blood pressure; hypertension; aged; J-shaped curve

(12BJZ02).

R544.1; R592

A

10.11915/j.issn.1671-5403.2015.08.129

2015?02?02;

2015?03?17

保健專項(xiàng)科研課題（12BJZ02）

孟威宏, E-mail: shuitianlianbi@sina.com