鹽攝入和心血管病風(fēng)險(xiǎn)剖析

1、周建成Dietary Sodium and Cardiovascular Disease Risk Measurement Matters食鹽攝入和心血管病風(fēng)險(xiǎn)論測(cè)定方法的重要性周建成引子回應(yīng)背景 高血壓是威脅美國(guó)人民生命安全的頭號(hào)殺手心血管病的常見(jiàn)且主要的危險(xiǎn)因素。減少過(guò)量的鹽攝入能夠降低血壓，尤其是高血壓人群。 如果按照每日攝入鈉超過(guò)2300mg注計(jì)算，超九成美國(guó)人食鹽超量。所以各醫(yī)療衛(wèi)生機(jī)構(gòu)推薦每日鈉 控制在2300mg以內(nèi)以取得公眾健康獲益。 然而這種獲益正遭到質(zhì)疑：有研究表明低鹽攝入跟心血管病風(fēng)險(xiǎn)增加有關(guān) 在科學(xué)上，使用不同等級(jí)研究方法出現(xiàn)結(jié)論南轅北轍的案例不在少數(shù)，研究鹽攝入的方法

2、很多，精確測(cè)定很重要。注 Department of Health and Human Services, Department of Agriculture. Dietary guidelines for Americans 2015-2020. 8thed. 2015Low Sodium Intake and Increased Cardiovascular Risk:Association or Causation? In some analyses of these studies, both low and high intakes of sodium, as compared wi

3、th “usual” intake (defined most recently as 3000 to 5000 mg per day), were associated with an increased risk of cardiovascular disease. Prospective cohort studies can have significant methodological problems that alter the direction of the results. 對(duì)一些研究的分析顯示：相對(duì)于正常值（3000mg-5000mg），無(wú)論低鹽還是高鹽攝入都與心血管病風(fēng)險(xiǎn)

4、增加有關(guān)。前瞻性的隊(duì)列研究可能存在導(dǎo)致相反結(jié)果的方法學(xué)問(wèn)題。THE BRADFORD HILL CRITERIAStrengthWhat is the degree to which the exposure (low sodium intake) is associatedwith the outcome (cardiovascular disease)?In studies reporting an apparent J- or U-shaped relationship between sodium intake and one or more cardiovascular outcom

5、es, a higher proportion of participants in the low-sodium groups than in groups with other intake levels had diabetes, hypertension, preexisting cardiovascular disease, or more severe chronic illness at baseline. Patients who are ill may have lower sodium intake because they eat less or are trying t

6、o eat lower-sodium foods, which may lead to a noncausal association between low sodium intake and increased cardiovascular events.在報(bào)告鹽攝入和心血管事件呈J-型或者U-型關(guān)系的研究中，低鹽攝入組中有糖尿病、高血壓、心血管病或者其他慢性疾病的比例明顯高于基線。這些人可能因?yàn)槌缘纳倩蛘邍L試低鹽飲食，導(dǎo)致了低鹽攝入與增加的心血管事件之間的非因果關(guān)系StrengthIn some studies, the investigators did not take into a

7、ccount the presence or absence of chronic kidney disease as a factor in this association. Patients with chronic kidney disease, on average, have lower sodium intake and an increased risk of death. In many studies, other factors, such as calorie intake and physical activity, are poorly measured, and

8、adjustment does not eliminate confounding in such cases.某些研究中，研究者并未將慢性腎病列入影響因素，慢性腎病的病人平均鹽攝入低而死亡風(fēng)險(xiǎn)卻更高。許多研究中，卡路里攝入和體力活動(dòng)等因素很少測(cè)量，而且測(cè)算的時(shí)候并未去除這些混雜因素mortalitySodium intakeCKDStrength Analyses showing a J- or U-shaped relationship between sodium intake and one or more cardiovascular outcomes in general popu

9、lation samples used convenient but potentially biased methods to estimate individual intake. Multiple, nonconsecutive, 24-hour urine collections are the gold standard for assessing sodium intake. Some sodium measures, such as spot urine tests, unacceptably overestimate individual intake at low level

10、s and underestimate intake at high levels. In association studies, individual level accuracy matters. Having large numbers of participants does not trump concerns about ascertainment bias and misclassification.分析顯示鹽攝入和若干心血管事件呈J-型或者U-型關(guān)系的例子中，使用方便的但存在潛在導(dǎo)致結(jié)果偏倚的方法來(lái)評(píng)估個(gè)體鹽攝入。多次，非連續(xù)的，24-h尿鈉法是評(píng)估鹽攝入的金標(biāo)準(zhǔn)。一些方法，

11、例如點(diǎn)尿鈉測(cè)定，在低鹽攝入會(huì)高估結(jié)果，而在高鹽攝入則出現(xiàn)低估。在相關(guān)性研究中，對(duì)個(gè)體水平的精確測(cè)定很重要。納入樣本量大并不能確保不產(chǎn)生偏倚和錯(cuò)分類ConsistencyHas the association “been repeatedly observed by different persons,in different places, circumstances, and times?”In keeping with the linear doseresponse effect of sodium intake on blood pressure and of blood pressur

12、e on the risk of cardiovascular disease or death, analyses of general population cohort studies, or of specific groups, such as patients with chronic kidney disease, support a positive linear association from low to high levels of sodium intake and an increased risk of cardiovascular disease. 和鹽攝入與血

13、壓之間以及血壓與心血管病或死亡的風(fēng)險(xiǎn)之間的量效關(guān)系一致，對(duì)人群的隊(duì)列研究，或?qū)μ囟▉喗M，例如慢性腎病病人的研究支持鹽攝入與心血管病風(fēng)險(xiǎn)增加呈現(xiàn)從低到高的線性相關(guān)ConsistencyOne analysis indicated that the rate of death from cardiovascular disease increased linearly by 1% with every 230-mg increase in daily sodium intake (4% for every 1000 mg). This association, however, is probab

14、ly attenuated by reporting and coding errors in dietary measures of sodium intake and, for urinary biomarkers, the use of one or two consecutive 24-hour urine collections. Because the foods we eat vary from day to day, a persons variability in sodium intake can be as great or greater than interperso

15、nal variability. Even on a fixed sodium intake, the day-to-day variance in 24-hour urine sodium excretion may be up to 40% of a persons average long term sodium excretion.一個(gè)分析顯示每日鹽攝入每增加230mg,心血管病死亡率增加1%。但這種相關(guān)性會(huì)由于鹽攝入測(cè)定方法的選用不當(dāng)而削弱。因?yàn)槲覀兠咳整}攝入差異很大，另外即使攝入不變，每日鹽排泄量也有很大波動(dòng)ConsistencyUsing the gold-standard me

16、asure of individual sodium intake multiple (three to seven) nonconsecutive 24-hour urine collections over 1.5 to 4 years the Trials of Hypertension Prevention (TOHP) showed a “l(fā)inear 17% increase in cardiovascular disease risk per 1000 mg per day increase in sodium” from levels starting at 1500 mg p

17、er day among 2275 participants, approximately 10% of whom had a sodium intake of less than 2300 mg (P = 0.05).The association reported in the TOPH analysis is much stronger than that reported in studies based on less accurate measurement methods持續(xù)1.5-4年使用金標(biāo)準(zhǔn)測(cè)定鹽攝入（多次（3-7次）非連續(xù)24-h尿鈉測(cè)定）的高血壓預(yù)防試驗(yàn)（TOHP）表明

18、：鹽攝入每增加1000mg,心血管病風(fēng)險(xiǎn)增加17%，納入病例的鹽攝入水平從1500mg-2275mg，這其中有近10%的病例鹽攝入低于2300mg，TOHP報(bào)道的這種的相關(guān)性強(qiáng)度要比使用非精確測(cè)定方法的研究強(qiáng)。Specificity Is the observed association limited to the exposure and outcome?An association of low or high sodium intake with all-cause mortality is unlikely. The fact that two thirds of deaths in

19、 the United States are from causes other than cardiovascular disease ought to mean that sodium consumption should correlate more tightly with cardiovascular death than with death from any cause. In a 20-year follow-up of participants in one study, the previously reported association of low sodium in

20、take with increased cardiovascular mortality was no longer significant. The association between estimated low sodium intake and all-cause mortality resulted from an increased risk of death from causes other than cardiovascular disease.低鹽和高鹽攝入和全因死亡率的相關(guān)性是不可能的。美國(guó)2/3的死亡是由心血管病以外的原因引起的，這意味著相對(duì)于全因死亡率，鹽的攝入跟心

21、血管死亡關(guān)系更緊。在一項(xiàng)20年的隨訪研究中，之前報(bào)道的低鹽攝入和心血管死亡率增加之間的相關(guān)性不明顯。估計(jì)的低鹽攝入和全因死亡率之間的關(guān)系是由于心血管病之外的的死亡風(fēng)險(xiǎn)增加。Specificity In this study, sodium measurement was a single 24-hour urine collection, and participants were advised to avoid “excessively salty food” for 4 to 5 days preceding collection. The authors concluded, “The

22、 inconsistent results cast doubt on whether a single measurement can reliably predict mortality over a prolonged follow-up period.在這項(xiàng)研究中，鹽攝入測(cè)定方法是單次24-h尿鈉測(cè)定，受試者被建議采樣前4到5天避免高鹽飲食。作者總結(jié)說(shuō)：不一致的結(jié)果讓人懷疑單次（尿鈉）測(cè)定用于預(yù)測(cè)長(zhǎng)期隨訪的死亡率是否可靠Temporality“Does a particular diet lead to disease or do early stages of disease lea

23、d tothose with peculiar dietetic habits?”In the United States, a low-sodium diet is uncommon and hard to follow, given the nature of dietary patterns, the ubiquity of salt in the food supply, and the high correlation between sodium and calorie intake. Even among people who are trying to lower their

24、intake because of cardiovascular risk, it is possible that sodium intake was not reduced soon enough, or for long enough, to prevent subsequent adverse health outcomes. These possibilities are of particular concern in studies with short follow-up.在美國(guó)，鑒于飲食模式、食物中食鹽的廣泛存在以及食鹽和卡路里的緊密聯(lián)系，低鹽飲食不常見(jiàn)也不好施行。即使對(duì)于某

25、些因心血管風(fēng)險(xiǎn)而嘗試減少鹽攝入的人們，也很難足夠快、足夠久減少鹽攝入以預(yù)防不良的健康后果。這些都是短期隨訪研究中所要特別注意的問(wèn)題。TemporalityIn 2003, the United Kingdom set voluntary sodium target levels for food manufacturers. From 2001 through 2011 in the United Kingdom, the average daily sodium intake among adults between the ages of 19 and 64 years decreased

26、 by about 15% (or by 560 mg), the average systolic blood pressure decreased by 3.0 mm Hg, and the rate of death from stroke or ischemic heart disease decreased by approximately 40%.英國(guó)在2003年為食品加工行業(yè)設(shè)定了自愿的限鹽目標(biāo)。從2001年到2011年，19到64歲成人的鹽攝入下降了15%（560mg），平均收縮壓下降了3.0mmHg，由于中風(fēng)和缺血性心臟病導(dǎo)致的死亡率下降近40%。Biologic Gradi

27、ent （DoseResponse） Is there a doseresponse relationship between the exposure and outcome?The purported J- or U-shaped association between sodium intake and the risk of cardiovascular disease could mean that blood pressure does not decrease below a certain threshold of sodium intake (e.g., 2300 mg pe

28、r day) or that an additional biologic risk factor is the cause.傳說(shuō)中的鹽攝入和心血管病風(fēng)險(xiǎn)之間的J-型或者U-型關(guān)系也許意味著當(dāng)鹽攝入量處于某個(gè)臨界值（例如：2300mg/天）血壓值將不再下降或者包含其他的生物風(fēng)險(xiǎn)因素risk of CDSodium intake2300mg/dBiologic Gradient （DoseResponse）A significant doseresponse decrease in blood pressure is observed in rigorously controlled trial

29、s with three or more confirmed levels of dietary sodium, down to about 1200 to 1500 mg per day, consumed for at least 4 weeks. Thus, a threshold effect at 2300 mg seems unlikely.一項(xiàng)嚴(yán)格對(duì)照試驗(yàn)觀察到食鹽和血壓下降之間呈現(xiàn)明顯的量效關(guān)系，該試驗(yàn)采用三項(xiàng)或更有力證據(jù)水平的鹽測(cè)定方法，鹽攝入量低至1200mg到1500mg每天，長(zhǎng)達(dá)4周以上。所以，2300mg/d不太可能是閾值。注：HIGH:150mmolNa（ 3.45

30、g）、INTERMEDIATE:50-150mmolNa（1.15-3.45g）、LOW:50mmolNa（ 1.15g）Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344: 3-10.Biologic Gradient （DoseResponse）Hence, if a lower sodium intake is associated with higher cardiov

31、ascular risk, it must be adversely affecting some major risk factor for cardiovascular disease. However, the evidence does not support such a conclusion, as discussed below.由此（鹽攝入與血壓下降之間呈顯著量效關(guān)系），如果低鹽攝入與更高的心血管病風(fēng)險(xiǎn)相關(guān)，它一定是通過(guò)影響心血管病的某些主要風(fēng)險(xiǎn)因素。然而，下面的討論的證據(jù)并不支持這一結(jié)論。Plausibility Is there a physiological basis

32、for the observed association?Some authors suggest that low sodium intake increases levels of cholesterol, triglycerides, renin, aldosterone, and catecholamine, a hypothesis that purports to explain the association between low sodium intake and increased cardiovascular risk. The physiologic response

33、to a marked acute sodium restriction is increased aldosterone and angiotensin levels, which increases the reabsorption of sodium and water and maintains the electrolyte balance. However, this readjustment is temporary and unlikely to have population effects.有的作者認(rèn)為低鹽攝入提高膽固醇、甘油三酯、腎素、醛固酮和兒茶酚胺水平，這或許可以用來(lái)

34、解釋低鹽攝入和心血管風(fēng)險(xiǎn)增加之間的相關(guān)性。對(duì)急性的限鹽措施的生理性反射是醛固酮和血管緊張素水平的提高，以增加鈉和水的重吸收，并且維持電解質(zhì)平衡。然而，這種再調(diào)整是暫時(shí)的，不太可能對(duì)人群產(chǎn)生影響。PlausibilityWhen analyses are limited to interventions lasting at least 4 weeks, reduced sodium intake does not adversely affect blood lipids, catecholamine levels, or renal function, and renin and aldos

35、terone effects are as expected as a physiologic response to blood-pressure lowering. Some investigators suggest that low sodium intake may increase insulin resistance. According to systematic reviews and meta-analyses, sodium reduction does not affect fasting glucose levels or consistently affect in

36、sulin resistance, nor does it affect glycated hemoglobin levels in patients with diabetes.在對(duì)持續(xù)至少4周以上的干預(yù)試驗(yàn)分析表明，限鹽并不能通過(guò)影響血脂、兒茶酚胺水平、腎功能、腎素和醛固酮產(chǎn)生血壓下降效應(yīng)。有的研究人員認(rèn)為低鹽攝入有可能增加胰島素抵抗。系統(tǒng)評(píng)價(jià)和meta-分析顯示，限鹽并不能影響空腹血糖，也不會(huì)持續(xù)產(chǎn)生胰島素抵抗，也不會(huì)影響糖尿病病人糖化血紅蛋白水平。PlausibilityConversely, sodium reduction has health benefits beyond bl

37、ood-pressure lowering, such as improved creatinine clearance in patients with diabetes and a lower risk of proteinuria in those with chronic kidney disease相反的，限鹽對(duì)健康的益處不止血壓下降，還增加糖尿病病人的肌酐清除率、降低慢性腎病病人蛋白尿的風(fēng)險(xiǎn)Coherence Does the “cause-and-effect interpretation” of the association “seriously conflict”with

38、“generally known facts about the natural history and biology ofthe disease”?The association between low sodium intake and increased cardiovascular risk conflicts with the evidence of the effects of sodium reduction on blood pressure and of blood-pressure reduction on the risk of cardiovascular disea

39、se低鹽攝入和心血管風(fēng)險(xiǎn)增加之間相關(guān)性與限鹽降壓和降壓對(duì)心血管病風(fēng)險(xiǎn)之間的影響的證據(jù)相矛盾CoherenceIn addition, physiological studies in animals and humans indicate that sodium reduction could reduce cardiovascular risk through mechanisms independent of blood pressure, such as improved endothelial functioning, decreased arterial stiffness, and

40、 decreased left ventricular mass另外，在動(dòng)物和人體的生理學(xué)研究都表明限鹽能通過(guò)降低血壓以外的途徑降低心血管風(fēng)險(xiǎn)，比如提高內(nèi)皮功能，降低動(dòng)脈硬度，減少左心容積Experiment “Is the frequency of associated events outcomes” affected by actions toprevent the exposure?Although few randomized, controlled trials have examined the effects of sodium reduction on cardiovascu

41、lar events, available evidence suggests that sodium reduction lowers the risk of cardiovascular disease. Diet, like other complex behaviors, is difficult to fit into the guidelines of pharmaceutical trials, since sustaining high compliance can be challenging, blinding is infeasible, and interactions

42、 between dietary components are probable.雖然僅有少部分研究限鹽對(duì)心血管事件影響的隨機(jī)對(duì)照試驗(yàn)，但是目前證據(jù)表明限鹽可以降低心血管病的風(fēng)險(xiǎn)。跟其他復(fù)雜行為相似，飲食在藥學(xué)試驗(yàn)中很做到一致，由于維持一致很難，盲法就不可行，并且各飲食成分之間還存在相互作用。ExperimentWhen data from six trials involving 5912 participants with both normal levels of blood pressure and hypertension were pooled, sodium reduction

43、was shown to result in a significant (23%) decrease in cardiovascular events at the longest follow-up. The direction of the effect in the four larger trials was toward the prevention of cardiovascular disease. These trials included TOHP I and II, TONE (Trial of Nonpharmacologic Interventions in the

44、Elderly), and a trial involving Taiwanese veterans. Among four of these trials assessing compliance, the average daily sodium reduction was 529 to 1010 mg. In the trials that included blood-pressure measurements, the average decrease in systolic blood pressure was 1.3 to 4.2 mm Hg對(duì)6項(xiàng)包含5912個(gè)病例、正常血壓和高

45、血壓合并的試驗(yàn)數(shù)據(jù)分析表明，限鹽在最長(zhǎng)隨訪人群心血管事件顯著下降（23%）。其中4項(xiàng)大型試驗(yàn)死亡結(jié)果指向預(yù)防心血管病發(fā)生。這些試驗(yàn)包括TOHPI 和 THOPII ，TONE（老年人群非藥學(xué)干預(yù)試驗(yàn)），還有一項(xiàng)包括臺(tái)灣老兵的試驗(yàn)。這其中四項(xiàng)平均每日鹽攝入減少量為529mg-1010mg，在包含血壓測(cè)量的試驗(yàn)中，收縮壓值下降1.3-4.2mm HgAnalogy Does an exposure with a similar action (physiologically) cause the outcome?If low sodium intake increased cardiovascul

46、ar risk, we would expect that other interventions with analogous mechanisms for blood-pressure-lowering effects (such as diuretics) might also increase the risk. However, analogously to sodium reduction, the use of antihypertensive medications, including diuretics, is associated with a 20% reduction

47、 in cardiovascular events and a 13% reduction in all-cause mortality for each decrease of 10 mm Hg in systolic blood pressure, according to analyses of 123 randomized trials involving 613,815 participants如果低鹽攝入增加心血管風(fēng)險(xiǎn)，我們可以推測(cè)其他具有相似降壓作用的機(jī)制（例如利尿劑）也許也會(huì)增加風(fēng)險(xiǎn)。然而，通過(guò)123項(xiàng)包含613，815例病例的隨機(jī)試驗(yàn)發(fā)現(xiàn)，類似于限鹽，使用抗高血壓藥物，包括利

48、尿劑，收縮壓每降低10mmg Hg，能降低20%心血管事件和13%的全因死亡率。Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387: 957-67Future Directions?The application of Hills criteria to the putative association between low sodium intake and an increase

49、d risk of cardiovascular disease indicates that the association is not causal. Measurement matters. Because of measurement challenges and day-to-day variability in sodium intake, estimating population averages is far less subject to error than estimating individual intake. That fact may explain why

50、countries with successful public health interventions that reduce sodium intake in the population show reductions in blood pressure and cardiovascular disease, whereas prospective cohort studies using short-term individual measures sometimes do not.應(yīng)用HILL標(biāo)準(zhǔn)推斷低鹽攝入和心血管病風(fēng)險(xiǎn)增加之間的相關(guān)性不是因果關(guān)系。測(cè)定方法很重要。由于測(cè)定方法的

51、困難以及每日飲食中鹽攝入的差異，對(duì)人群平均水平的估測(cè)比個(gè)體更客觀。這也許可以用來(lái)解釋為什么某些國(guó)家成功采取限鹽措施對(duì)公眾健康干預(yù)，取得了血壓下降和心血管病減少，而短期前瞻性隊(duì)列研究有時(shí)卻不能。Future Directions?There is strong evidence of a linear, doseresponse effect of sodium reduction on blood pressure. In addition, the evidence shows that sodium reduction prevents cardiovascular disease. Th

52、is evidence is based on findings from prospective cohort studies with accurate measurement of usual sodium intake, analyses of long-term intervention trials, human and animal physiological studies, and public health intervention sat the population level.強(qiáng)有力的證據(jù)表明限鹽對(duì)血壓之間存在線性量效關(guān)系。此外，限鹽預(yù)防心血管病。這個(gè)證據(jù)是基于精確測(cè)定鹽攝入的前瞻性隊(duì)列研究，長(zhǎng)期的干預(yù)試驗(yàn)，人和動(dòng)物生理學(xué)研究，群體水平的公共健康干預(yù)Future Directions?Undue emphasis on observational studies with large numbers of participants but invalid measurement of sodium intake and other methodologic