盐摄入和心血管病风险剖析

1、周建成Dietary Sodium and Cardiovascular Disease Risk Measurement Matters食盐摄入和心血管病风险论测定方法的重要性周建成引子回应背景 高血压是威胁美国人民生命安全的头号杀手心血管病的常见且主要的危险因素。减少过量的盐摄入能够降低血压，尤其是高血压人群。 如果按照每日摄入钠超过2300mg注计算，超九成美国人食盐超量。所以各医疗卫生机构推荐每日钠 控制在2300mg以内以取得公众健康获益。 然而这种获益正遭到质疑：有研究表明低盐摄入跟心血管病风险增加有关 在科学上，使用不同等级研究方法出现结论南辕北辙的案例不在少数，研究盐摄入的方法

2、很多，精确测定很重要。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. 对一些研究的分析显示：相对于正常值（3000mg-5000mg），无论低盐还是高盐摄入都与心血管病风险

4、增加有关。前瞻性的队列研究可能存在导致相反结果的方法学问题。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.在报告盐摄入和心血管事件呈J-型或者U-型关系的研究中，低盐摄入组中有糖尿病、高血压、心血管病或者其他慢性疾病的比例明显高于基线。这些人可能因为吃的少或者尝试低盐饮食，导致了低盐摄入与增加的心血管事件之间的非因果关系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，研究者并未将慢性肾病列入影响因素，慢性肾病的病人平均盐摄入低而死亡风险却更高。许多研究中，卡路里摄入和体力活动等因素很少测量，而且测算的时候并未去除这些混杂因素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.分析显示盐摄入和若干心血管事件呈J-型或者U-型关系的例子中，使用方便的但存在潜在导致结果偏倚的方法来评估个体盐摄入。多次，非连续的，24-h尿钠法是评估盐摄入的金标准。一些方法，

11、例如点尿钠测定，在低盐摄入会高估结果，而在高盐摄入则出现低估。在相关性研究中，对个体水平的精确测定很重要。纳入样本量大并不能确保不产生偏倚和错分类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. 和盐摄入与血

13、压之间以及血压与心血管病或死亡的风险之间的量效关系一致，对人群的队列研究，或对特定亚组，例如慢性肾病病人的研究支持盐摄入与心血管病风险增加呈现从低到高的线性相关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.一个分析显示每日盐摄入每增加230mg,心血管病死亡率增加1%。但这种相关性会由于盐摄入测定方法的选用不当而削弱。因为我们每日盐摄入差异很大，另外即使摄入不变，每日盐排泄量也有很大波动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 “linear 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持续1.5-4年使用金标准测定盐摄入（多次（3-7次）非连续24-h尿钠测定）的高血压预防试验（TOHP）表明

18、：盐摄入每增加1000mg,心血管病风险增加17%，纳入病例的盐摄入水平从1500mg-2275mg，这其中有近10%的病例盐摄入低于2300mg，TOHP报道的这种的相关性强度要比使用非精确测定方法的研究强。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.低盐和高盐摄入和全因死亡率的相关性是不可能的。美国2/3的死亡是由心血管病以外的原因引起的，这意味着相对于全因死亡率，盐的摄入跟心

21、血管死亡关系更紧。在一项20年的随访研究中，之前报道的低盐摄入和心血管死亡率增加之间的相关性不明显。估计的低盐摄入和全因死亡率之间的关系是由于心血管病之外的的死亡风险增加。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.在这项研究中，盐摄入测定方法是单次24-h尿钠测定，受试者被建议采样前4到5天避免高盐饮食。作者总结说：不一致的结果让人怀疑单次（尿钠）测定用于预测长期随访的死亡率是否可靠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.在美国，鉴于饮食模式、食物中食盐的广泛存在以及食盐和卡路里的紧密联系，低盐饮食不常见也不好施行。即使对于某

25、些因心血管风险而尝试减少盐摄入的人们，也很难足够快、足够久减少盐摄入以预防不良的健康后果。这些都是短期随访研究中所要特别注意的问题。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%.英国在2003年为食品加工行业设定了自愿的限盐目标。从2001年到2011年，19到64岁成人的盐摄入下降了15%（560mg），平均收缩压下降了3.0mmHg，由于中风和缺血性心脏病导致的死亡率下降近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.传说中的盐摄入和心血管病风险之间的J-型或者U-型关系也许意味着当盐摄入量处于某个临界值（例如：2300mg/天）血压值将不再下降或者包含其他的生物风险因素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.一项严格对照试验观察到食盐和血压下降之间呈现明显的量效关系，该试验采用三项或更有力证据水平的盐测定方法，盐摄入量低至1200mg到1500mg每天，长达4周以上。所以，2300mg/d不太可能是阈值。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（盐摄入与血压下降之间呈显著量效关系），如果低盐摄入与更高的心血管病风险相关，它一定是通过影响心血管病的某些主要风险因素。然而，下面的讨论的证据并不支持这一结论。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.有的作者认为低盐摄入提高胆固醇、甘油三酯、肾素、醛固酮和儿茶酚胺水平，这或许可以用来

34、解释低盐摄入和心血管风险增加之间的相关性。对急性的限盐措施的生理性反射是醛固酮和血管紧张素水平的提高，以增加钠和水的重吸收，并且维持电解质平衡。然而，这种再调整是暂时的，不太可能对人群产生影响。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.在对持续至少4周以上的干预试验分析表明，限盐并不能通过影响血脂、儿茶酚胺水平、肾功能、肾素和醛固酮产生血压下降效应。有的研究人员认为低盐摄入有可能增加胰岛素抵抗。系统评价和meta-分析显示，限盐并不能影响空腹血糖，也不会持续产生胰岛素抵抗，也不会影响糖尿病病人糖化血红蛋白水平。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，限盐对健康的益处不止血压下降，还增加糖尿病病人的肌酐清除率、降低慢性肾病病人蛋白尿的风险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低盐摄入和心血管风险增加之间相关性与限盐降压和降压对心血管病风险之间的影响的证据相矛盾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，在动物和人体的生理学研究都表明限盐能通过降低血压以外的途径降低心血管风险，比如提高内皮功能，降低动脉硬度，减少左心容积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.虽然仅有少部分研究限盐对心血管事件影响的随机对照试验，但是目前证据表明限盐可以降低心血管病的风险。跟其他复杂行为相似，饮食在药学试验中很做到一致，由于维持一致很难，盲法就不可行，并且各饮食成分之间还存在相互作用。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对6项包含5912个病例、正常血压和高

45、血压合并的试验数据分析表明，限盐在最长随访人群心血管事件显著下降（23%）。其中4项大型试验死亡结果指向预防心血管病发生。这些试验包括TOHPI 和 THOPII ，TONE（老年人群非药学干预试验），还有一项包括台湾老兵的试验。这其中四项平均每日盐摄入减少量为529mg-1010mg，在包含血压测量的试验中，收缩压值下降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如果低盐摄入增加心血管风险，我们可以推测其他具有相似降压作用的机制（例如利尿剂）也许也会增加风险。然而，通过123项包含613，815例病例的随机试验发现，类似于限盐，使用抗高血压药物，包括利

48、尿剂，收缩压每降低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.应用HILL标准推断低盐摄入和心血管病风险增加之间的相关性不是因果关系。测定方法很重要。由于测定方法的

51、困难以及每日饮食中盐摄入的差异，对人群平均水平的估测比个体更客观。这也许可以用来解释为什么某些国家成功采取限盐措施对公众健康干预，取得了血压下降和心血管病减少，而短期前瞻性队列研究有时却不能。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.强有力的证据表明限盐对血压之间存在线性量效关系。此外，限盐预防心血管病。这个证据是基于精确测定盐摄入的前瞻性队列研究，长期的干预试验，人和动物生理学研究，群体水平的公共健康干预Future Directions?Undue emphasis on observational studies with large numbers of participants but invalid measurement of sodium intake and other methodologic