庫(kù)珀中心縱向研究：有氧運(yùn)動(dòng)的靈魂

Stephen W.Farrell,Laura F.DeFina,閻海（譯）朱為模審校

0 前言

規(guī)律性的體力活動(dòng)能夠有效降低多種類(lèi)型疾病發(fā)病率和死亡率。雖然，從目前來(lái)看，大家已經(jīng)對(duì)這二者的關(guān)系達(dá)成了共識(shí)，但幾十年前幾乎沒(méi)有任何證據(jù)支持這一觀(guān)點(diǎn)。20世紀(jì)50年代末到60年代肯尼斯·庫(kù)珀（Kenneth H.Cooper）博士在美國(guó)空軍任職期間，確信經(jīng)常鍛煉是預(yù)防疾病和保持身體健康的關(guān)鍵之一。他于1970年12月建立庫(kù)珀研究所，因?yàn)樗乐挥芯脑O(shè)計(jì)的研究才能證明他認(rèn)定的事實(shí)。因此，當(dāng)庫(kù)珀診所在此后不久剛剛開(kāi)業(yè)時(shí)，庫(kù)珀博士開(kāi)始對(duì)客戶(hù)進(jìn)行細(xì)致記錄，并有遠(yuǎn)見(jiàn)地意識(shí)到需要追蹤這些客戶(hù)的發(fā)病率和死亡率。于是，有氧運(yùn)動(dòng)中心縱向研究（Aerobics Center Longitudinal Study，ACLS）誕生了，ACLS的主要目的是檢查預(yù)防醫(yī)學(xué)中心的心肺健康（Cardiorespiratory fitness，CRF）與健康結(jié)果之間的關(guān)系。值得注意的是，之前與運(yùn)動(dòng)相關(guān)的研究主要集中在身體活動(dòng)的行為方面，而那時(shí)身體活動(dòng)是通過(guò)問(wèn)卷調(diào)查估算的。與身體活動(dòng)不同，心肺健康可以通過(guò)最大跑臺(tái)運(yùn)動(dòng)測(cè)試 （Maximal Treadmill Exercise Testing）客觀(guān)測(cè)量。在A(yíng)CLS啟動(dòng)時(shí)，并沒(méi)有關(guān)于心肺健康水平與重要健康結(jié)果之間關(guān)聯(lián)的文獻(xiàn)數(shù)據(jù)。因此，最大跑臺(tái)運(yùn)動(dòng)測(cè)試很快成為ACLS的一個(gè)組成部分。

0 Background

Regular physical activity provides substantial protection against many types of morbidity and mortality.While this seems intuitive today,there was little evidence to support this opinion several decades ago.During his time in the U.S.Air Force in the late 1950’s and 1960’s,Dr.Kenneth Cooper became convinced that regular exercise was one of the keys to disease prevention and good health.He chartered The Cooper Institute in December,1970 because he knew that only well-designed research studies would prove what he already believed to be true.Accordingly,when the Cooper Clinic first opened shortly thereafter,Dr.Cooper began to keep meticulous records of his patients and had the foresight to realize the need to track these patients for morbidity and mortality over time.Hence,the Aerobics Center Longitudinal Study(ACLS)was born.The major purpose of the ACLS was to examine the relationship between cardiorespiratory fitness and health outcomes in a preventive medicine center.It is important to note that previous exercise-related studies focused on physical activity,which is a behavior.At that time,physical activity was estimated by utilizing questionnaires.Unlike physical activity,cardiorespiratory fitness is a characteristic that can be objectively measured via maximal treadmill exercise testing.At the time the ACLS was launched,there was no data in the literature regarding the association of cardiorespiratory fitness level with important health outcomes.Thus,the maximal treadmill exercise test quickly became an integral portion of the ACLS.

1 ACLS與庫(kù)珀中心縱向研究之間的差異

ACLS是評(píng)估健康生活方式選擇與各種結(jié)果（包括疾病、殘疾和死亡率）之間關(guān)系的高效資源。庫(kù)珀中心縱向研究（CooperCenterLongitudinalStudy，CCLS）代表了ACLS的成熟和擴(kuò)展版本，增加了變量、生物材料和更多的結(jié)果 （截至2014年的新增的死亡率，醫(yī)療保險(xiǎn)數(shù)據(jù)和德克薩斯癌癥登記處數(shù)據(jù)）。CCLS的整體樣本量明顯大于A(yíng)CLS，因此具有更多的發(fā)病率和死亡率數(shù)據(jù)。

兩個(gè)研究的數(shù)據(jù)之間也存在其他重要差異。CCLS數(shù)據(jù)集額外包含血液指標(biāo) （包括維生素D水平、Omega-3指數(shù)、肝炎篩查），老年人篩查[包括蒙特利爾認(rèn)知評(píng)估（Montreal Cognitive Assessment，Mo-CA）和起立行走測(cè)試（Get Up and Go）評(píng)估]，高敏感性心肌肌鈣蛋白T水平，以及遺傳物質(zhì)。有關(guān)CCLS中新增內(nèi)容的更多詳細(xì)信息參見(jiàn)下文。

目前，有112 789名客戶(hù)累計(jì)訪(fǎng)問(wèn)庫(kù)珀診所達(dá)314 991次，已經(jīng)進(jìn)行了近250 000次最大跑臺(tái)運(yùn)動(dòng)測(cè)試；庫(kù)珀診所有著世界上最大的心肺健康數(shù)據(jù)庫(kù)。CCLS具有許多獨(dú)特且非常寶貴的特性：客戶(hù)通常是健康的、數(shù)據(jù)庫(kù)相當(dāng)大、進(jìn)行長(zhǎng)期隨訪(fǎng)。此外，仍需強(qiáng)調(diào)的是，最大跑臺(tái)運(yùn)動(dòng)測(cè)試提供了CRF的客觀(guān)測(cè)量結(jié)果。正如頂尖的健康專(zhuān)家們經(jīng)常說(shuō)的那樣：“你幾乎可以到任何地方去研究病人，但CCLS是你唯一可以研究健康人的地方。”

1 Differences betwe en the Aerobics Center LongitudinalStudyand theCooperCenter Longitudinal Study

The Aerobic s Center Longitudinal Study(ACLS)was a very productive resource in evaluating relationships between healthy lifestyle choices and a variety of outcomes including disease,disability,and mortality.The Cooper Center Longitudinal Study (CCLS)represents a matured and expanded version of the ACLS with added variables,biomaterials,and added outcomes(additional mortality through 2014,Medicare data,and Texas Cancer Registry).The overall sample size for CCLS is significantly larger than ACLS,and thus has a much greater amount of morbidity and mortality data.

Other important differences between the two data sets exist.The CCLS data set contains additional blood variables including vitamin D levels,the Omega-3 Index,hepatitis screens;geriatric screening including the Montreal Cognitive Assessment(MoCA)and Get Up and Go assessment;high sensitivity cardiac troponin T levels;and genetic material and.More detail regarding the additional information contained in the CCLS is provided below.

At the present time,there have been 314 991 Cooper Clinic visits by 112 789 patients.Nearly 250 000 maximal treadmill exercise tests have been administered;this represents the largestcardiorespiratory fitness database in the world.The CCLS has many unique and invaluable features.Patients are generally healthy,the data base is quite large,and there has been long-term follow-up.Additionally,it is important to reinforce that the maximal treadmill exercise test provides an objective measure of cardiorespiratory fitness (CRF).As is often stated by leading health experts,“You can go almost anywhere to study sick people;the CCLS is the only place you can go to study healthy people.”

2 CCLS人群

庫(kù)珀診所的客戶(hù)主要來(lái)源于自主入診人群，盡管大約三分之一的客戶(hù)是由其雇主推介而來(lái)。該診所每年診斷客戶(hù)6 000～8 000名，其中75%的客戶(hù)是回訪(fǎng)人群。臨床訪(fǎng)問(wèn)者之間的問(wèn)診間隔各有不同。一般而言，老年客戶(hù)往往比年輕客戶(hù)更頻繁地回訪(fǎng)。超過(guò)90%的臨床客戶(hù)同意參加CCLS。值得注意的是，庫(kù)珀診所的客戶(hù)并不代表美國(guó)人口的隨機(jī)樣本。庫(kù)珀診所客戶(hù)主要是非西班牙裔白人，受過(guò)高等教育，并且具有中上等級(jí)的社會(huì)經(jīng)濟(jì)地位。在CCLS數(shù)據(jù)庫(kù)中，男性的數(shù)量多于女性，比例約為3:1。因此，就整體美國(guó)人口的普適化而言，數(shù)據(jù)和研究結(jié)果存在一些局限性。然而，研究表明，CCLS參與者的CRF水平與美國(guó)一般人群的CRF水平非常接近[1,2]。圖1顯示了CCLS男性和女性的最大MET值代表的CRF，與選擇參加國(guó)家健康和營(yíng)養(yǎng)檢驗(yàn)調(diào)查（National Health and Nutrition Examination Survey，NHANES）的男性和女性的隨機(jī)樣本相比較的結(jié)果。

圖1 CCLS男性和女性的最大MET值代表的CRF與選擇參加國(guó)家健康和營(yíng)養(yǎng)檢驗(yàn)調(diào)查中男性和女性的隨機(jī)樣本比較Figure1 CRF Displayed as Maximal MET Values for CCLS Men and Women as Compared to A Random Sample of Men and Women Who Were Selected to Participate in NHANES

3 庫(kù)珀診所檢查

庫(kù)珀診所檢查的指標(biāo)根據(jù)客戶(hù)的年齡、性別和健康狀況而有所不同。因?yàn)閷?duì)每個(gè)客戶(hù)都收集數(shù)千個(gè)變量，本文只提及一些最重要的變量。在完成知情同意后，有關(guān)年齡、性別、婚姻狀況、種族、教育程度、當(dāng)前和之前的吸煙狀況、飲酒、就業(yè)狀況、當(dāng)前和之前的健康狀況和癥狀、家族病史、飲食習(xí)慣、身體活動(dòng)的信息（頻率、強(qiáng)度、持續(xù)時(shí)間和類(lèi)型）、訪(fǎng)問(wèn)次數(shù)、訪(fǎng)問(wèn)原因、安全習(xí)慣、心理狀態(tài)和藥物使用情況等信息均通過(guò)大范圍的醫(yī)療問(wèn)卷收集。雖然自2008年以來(lái)，藥物使用情況已經(jīng)常規(guī)地包含在數(shù)據(jù)庫(kù)中，但數(shù)據(jù)庫(kù)目前尚未提供診所早期的藥物使用情況。體重情況通過(guò)測(cè)量身體質(zhì)量指數(shù) （Body mass index，BMI）和體脂百分比來(lái)確定。從歷史上看，診所也采用流體靜力學(xué)評(píng)估體脂。血液檢查包括但不限于總膽固醇，HDL和LDL膽固醇，甘油三酯，葡萄糖，肝臟、腎臟和甲狀腺功能，電解質(zhì)，C反應(yīng)蛋白（C-reactive protein，CRP），同型半胱氨酸，維生素D和B12，前列腺特異性抗原 （Prostate specific antigen，PSA），總睪酮，全血細(xì)胞計(jì)數(shù)（Complete blood count，CBC），Omega-3指數(shù)和血紅蛋白A1c。尿液分析用以測(cè)量pH值、比重和酮類(lèi)變量，以及確定樣品中是否存在葡萄糖或蛋白質(zhì)，庫(kù)珀診所還會(huì)進(jìn)行視力、聽(tīng)力和肺功能測(cè)試。

庫(kù)珀診在做最大跑臺(tái)運(yùn)動(dòng)測(cè)試時(shí)所采用改良的Balke方案[3]，其運(yùn)動(dòng)持續(xù)時(shí)間比更常用的Bruce方案更長(zhǎng)。庫(kù)珀博士更喜歡改良的Balke方案，因?yàn)樗梢苑浅＞徛卦黾迂?fù)荷、更安全，并且比Bruce方案能提供更多的心電圖（Electrocardiograms，ECG）和血壓讀數(shù)。由于改良的 Balke方案比Bruce方案花費(fèi)的時(shí)間更長(zhǎng)，因此可以更清晰地分析健康水平。改良的Balke跑臺(tái)方案如下：第1分鐘速度為88 m/min，0%坡度；第2分鐘速度為88 m/min，2%坡度，此后每分鐘，坡度增加1%，從第25 min開(kāi)始坡度不變，速度每分鐘增加5.4 m/min。在跑臺(tái)運(yùn)動(dòng)測(cè)試期間收集的變量包括靜息心率和血壓，以及靜息心電圖。在運(yùn)動(dòng)測(cè)試期間和之后，收集關(guān)于心率、血壓和ECG反應(yīng)的數(shù)據(jù)。跑臺(tái)的最終速度和等級(jí)用于計(jì)算最大MET值，后者又反過(guò)來(lái)被用于確定基于年齡和性別的心肺健康類(lèi)別。

客戶(hù)也可以進(jìn)行影像學(xué)檢查，把其作為臨床檢查的一部分。自1997年以來(lái)，庫(kù)珀診所已對(duì)超過(guò)40 000名客戶(hù)進(jìn)行了超過(guò)77 000次計(jì)算機(jī)斷層掃描。對(duì)這部分人群進(jìn)行了廣泛監(jiān)測(cè)，以確定其縱向心血管健康狀況，并結(jié)合CCLS中的其他成像研究 （包括DEXA掃描、超聲心動(dòng)圖和頸動(dòng)脈研究）。一個(gè)生物資料庫(kù)（Biobank）從2008年9月開(kāi)始運(yùn)行，以建立一個(gè)DNA和血液樣本制品檔案，用以進(jìn)行基于與健康生活選擇相關(guān)的基因環(huán)境相互作用的研究。這項(xiàng)工作可以識(shí)別出與負(fù)責(zé)常見(jiàn)疾病有關(guān)的基因，并了解常見(jiàn)疾病治療和預(yù)防情況。目前，庫(kù)珀研究所存儲(chǔ)的DNA和冷凍血漿中存有超過(guò)13 000件個(gè)人標(biāo)本。

在庫(kù)珀診所獲取的CCLS數(shù)據(jù)不是基于系統(tǒng)的研究方案，而是基于前文提到的預(yù)防性健康評(píng)估和客戶(hù)特定的臨床建議，因此造成了隨訪(fǎng)間隔的可變性以及所有變量不同程度的可用性。正如前文所述，客戶(hù)回訪(fǎng)沒(méi)有特定的時(shí)間間隔。此外還存在包括客戶(hù)在訪(fǎng)問(wèn)時(shí)通常是健康的，但只有在他們生病時(shí)才重返診所等挑戰(zhàn)。CCLS數(shù)據(jù)庫(kù)由庫(kù)珀研究所維護(hù)，該組織是一個(gè)非營(yíng)利性的獨(dú)立研究中心，其總體研究目標(biāo)是評(píng)估生活方式行為和特征對(duì)健康的影響。庫(kù)珀研究所執(zhí)行嚴(yán)格的隱私保護(hù)措施。數(shù)據(jù)收集和知情同意過(guò)程每年均需要由庫(kù)珀研究所的機(jī)構(gòu)倫理審查委員會(huì)審查和批準(zhǔn)。

2 The CCLS Population

Cooper Clinic patients are primarily self-referred,although approximately one-third are referred by their employer.The Clinic sees between 6 000 and 8 000 patients per year;75%of whom are currently return patients.There are variable intervals between Clinic visits.Generally speaking,older patients tend to have their return visits more frequently than younger patients.Over 90%of Clinic patients consent to participate in the CCLS.We note that our patients do not represent a random sample of the United States population.Cooper Clinic patients are primarily non-Hispanic white,highly educated,and from middle to upper socioeconomic status.Within the CCLS database,men outnumber women by a margin of approximately 3 to 1.Thus,there are some limitations to our data and research findings in terms of generalization to the United States population as a whole.However,studies have shown that the CRF level among CCLS participants is very similar to that of the general United States population[1,2].The Figure be-low shows CRF displayed as maximal MET values for CCLS men and women as compared to a random sample of men and women who were selected to participate in the National Health and Nutrition Examination Survey(NHANES)

3 The Cooper Clinic Exam

The par ameters of the Cooper Clinic exam vary according to the patient’s age,gender,and health status.Because there are thousands of variables collected for each patient,only some of the most important ones will be mentioned here.After completing an informed consent,information regarding age,gender,marital status,ethnicity,education level,current and prior smoking status,alcohol use,employment status,current and prior health status and symptoms,family history of disease,dietary habits,physical activity (frequency,intensity,duration,and type),visit number,reason for visit,safety habits,psychological status,and medication use are collected via an extensive medical questionnaire.While medication use has been routinely included in the database since 2008,medication use from the early years of the Clinic is not currently available in the database.Body mass index(BMI)and percent body fat are measured to determine body weight status.Historically,the Clinic also using hydrostatic assessment of body fat.Blood tests include,but are not limited to total cholesterol,HDL and LDL cholesterol,triglycerides,glucose,liver,kidney,and thyroid function,electrolytes,C-reactive protein (CRP),homocysteine,vitamins D and B-12,prostate specific antigen(PSA),total testosterone,complete blood count(CBC),Omega-3 Index,and hemoglobin A1c.Urinalysis is done to measure the variables of pH,specific gravity,and ketones,as well as to determine if glucose or protein is present in the sample.Tests of vision,hearing,and pulmonary function are also performed.

TheCooperClinicusesthemodified-Balkeprotocol[3],which has a longer exercise duration than the more commonly used Bruce protocol.Dr.Cooper prefers the modified-Balke protocol because it increases workload very gradually,is safer,and allows time for a greater number of electrocardiograms (ECG)and blood pressure readings than the Bruce protocol.Because the modified-Balke test takes longer than the Bruce test,it results in a clearer distribution of fitness levels.The modified-Balke treadmill protocol is as follows:minute 1:88 meters/minute,0%elevation,minute 2:88 meters/minute,2%elevation.Each minute thereafter,a 1%increase in elevation occurs.At 25 minutes,speed is increased by 5.4 meters/minute each minute.Variables collected during the treadmill exercise test include resting heart rate and blood pressure,as well as resting ECG.During and following the exercise test,data on heart rate,blood pressure,and ECG responses are collected.The final speed and grade of the treadmill are used to calculate maximal MET values,which in turn are used to determine cardiorespiratory fitness category based on age and gender.

Patients may also undergo imaging studies as part of their Clinic exam.Since 1997,the Cooper Clinic has conducted more than 77 000 computed tomography scans on over 40 000 patients.Extensive surveillance has been conducted on this sub-population to ascertain their longitudinal cardiovascular health status.Other imaging studies that are incorporated into the CCLS include DEXA scans,echocardiograms,and carotid artery studies.A biobank has been in operation since September,2008 to establish an archive of DNA and blood product samples for research based on gene environment interaction related to healthy lifestyle choices.This effort can allow identification of genes responsible for common diseases and insights into their treatment and prevention.Currently,there are more than 13 000 individuals with specimens in the collection consisting of DNA and frozen plasma stored at The Cooper Institute.

Data acquired at the Cooper Clinic for the CCLS are not based on a systematic research protocol but rather on the previously mentioned preventive health evaluations and patient-specific clinical recommendations,resulting in variable follow-up intervals as well as different degrees of availability of all variables.As previously stated,there is no specific time interval between Cooper Clinic visits.Other challenges include the fact that patients are generally healthy at the time of their visit,and do not return to the Clinic only when they are ill.The CCLS database is maintained by The Cooper Institute,a nonprofit,independent research center with the overarching research goal of assessing the effect of lifestyle behaviors and characteristics on health outcomes.Privacy precautions are maintained through The Cooper Institute policies.The data collection and informed consent processes are reviewed and approved annually by the Institutional Review Board at The Cooper Institute.

4 死亡率監(jiān)測(cè)

截至2014年12月31日，通過(guò)NDIPlus（國(guó)家死亡指數(shù)）提供的信息，CCLS涉及的人群中有14 546人死亡。與美國(guó)人口的整體情況相似，CCLS中最常見(jiàn)的死亡原因是心血管疾病和癌癥。

4 Mortality Surveillance

Using the NDIPlus(National Death Index)service,14 546 deaths were recorded in the CCLS population through December 31,2014.Similar to the entire U.S.population,the most common causes of death in the CCLS are cardiovascular disease and cancer.

5 發(fā)病率監(jiān)測(cè)

庫(kù)珀中心除了使用回訪(fǎng)期間收集的數(shù)據(jù)外，還使用回信調(diào)查進(jìn)行發(fā)病率監(jiān)測(cè)。中心在1982年、1986年、1990年、1995年、1999年、2001年和 2004年向所有研究涉及到的人群郵寄了大量問(wèn)卷。并于2011年向接受電子束斷層掃描檢查的人群發(fā)送了一份調(diào)查問(wèn)卷。多年來(lái)問(wèn)卷的回收率為50%～75%。受訪(fǎng)者未完成調(diào)查的最常見(jiàn)原因是花費(fèi)了太多時(shí)間、客戶(hù)不感興趣，或客戶(hù)已搬家且沒(méi)有更新地址。

5 Morbidity Surveillance

In addition to using data collected during return visits,mail-back surveys are utilized for morbidity surveillance.Extensive questionnaires were mailed to the entire cohort in 1982,1986,1990,1995,1999,2001,and 2004.In 2011,a questionnaire was sent to the Electron Beam Tomography cohort.The response rate was 50%～75%throughout the years.The most common reasons given for not completing the survey were that it took too much time,the patient was not interested,or the patient moved and we did not have their new address.

5.1 醫(yī)療保險(xiǎn)（Medicare）

1971—2009年在庫(kù)珀診所接受檢查的大約29 000名CCLS參與者獲得了從1999年至2009年的醫(yī)療保險(xiǎn)資格，并與醫(yī)療保險(xiǎn)和醫(yī)療補(bǔ)助服務(wù)中心（Centers for Medicare and Medicaid Services，CMS）的數(shù)據(jù)庫(kù)相匹配。該群組的可用數(shù)據(jù)包括醫(yī)療保險(xiǎn)和醫(yī)療補(bǔ)助服務(wù)中心提供的經(jīng)過(guò)算法驗(yàn)證的慢性病癥庫(kù)中的疾病診斷和最早病兆出現(xiàn)日期。還有個(gè)人國(guó)際疾病分類(lèi) -9信息 （International Classification of Diseases-9）和住院及門(mén)診索賠的編碼及費(fèi)用等其他可用信息。醫(yī)療保險(xiǎn)數(shù)據(jù)為其他CCLS發(fā)病率監(jiān)測(cè)提供了獨(dú)特的補(bǔ)充，并有可能回答有關(guān)生活方式和預(yù)防對(duì)健康老齡化、生活質(zhì)量和醫(yī)療系統(tǒng)資源利用模式的長(zhǎng)期影響的問(wèn)題。值得注意的是，醫(yī)療保險(xiǎn)數(shù)據(jù)本質(zhì)上是行政性的，并不代替臨床診斷的結(jié)果或詳細(xì)的醫(yī)療記錄。例如，從醫(yī)療保險(xiǎn)數(shù)據(jù)中提取的中風(fēng)或高血壓的診斷不能提供血壓測(cè)量或診斷時(shí)的任何其他檢查結(jié)果。此外，由于醫(yī)療保險(xiǎn)數(shù)據(jù)僅在1999—2009年可用，因此通常難以獲取65歲以上參與者的完整醫(yī)療保險(xiǎn)體驗(yàn)。

5.1 Medicare

Approximately 29 000 CCLS participants examined at the Cooper Clinic between 1971-2009 who became eligible for Medicare between 1999 and 2009 were matched with the database at the Centers for Medicare and Medicaid Services(CMS).Data available for this subset of the cohort include disease diagnoses and earliest indication dates from the Chronic Condition Warehouse based on validated algorithms from the Centers for Medicare and Medicaid Services.Also available are individual International Classification of Diseases-9 and procedural codes for inpatient and outpatient claims as well as charges and other utilization information.Medicare data provides a unique complement to other CCLS morbidity surveillance and has the potential to answer questions regarding the long-term impact of lifestyle and prevention on patterns of healthy aging,quality of life,and healthcare system resource utilization.It is important to note that Medicare data is administrative in nature and does not represent a substitute for clinically adjudicated outcomes or detailed medical records.For example,a diagnosis of stroke or hypertension extracted from Medicare data cannot provide blood pressure measurement or any other exam results at the time of diagnosis.Also,since Medicare data is available only for an 11 year period beginning in 1999,the complete Medicare experience of a participant from age 65 is generally not captured.

5.2 德克薩斯州癌癥登記處

CCLS獲得了德克薩斯州癌癥登記處的數(shù)據(jù)，其中包括1995年至2007年期間德克薩斯州居民的CCLS被研究者中發(fā)生癌癥事件的信息，這些數(shù)據(jù)確定了約6 100例癌癥。

5.2 Texas Cancer Registry

Data from the Texas Cancer Registry has been obtained with information on incident cancer cases among CCLS patients who were Texas residents between 1995 and 2007.With this data,we identified approximately 6 100 incident cancers.

6 心肺健康的健康益處

在過(guò)去47年中，CCLS數(shù)據(jù)顯示，具有中高水平的心肺功能與許多重要的健康益處相關(guān)，包括降低全因、心血管和癌癥死亡率。從發(fā)病率的角度來(lái)看，保持健康與降低冠心病、中風(fēng)、Ⅱ型糖尿病、代謝綜合征、高血壓、某些癌癥、抑郁癥和記憶喪失的風(fēng)險(xiǎn)有關(guān)。下文將對(duì)這些研究進(jìn)行充分討論。

6 Health Benefits of Cardiorespiratory Fitness

Over the past 47 years,CCLS data has shown that having a moderate to high level of measured cardiorespiratory fitness is associated with a number of significant health benefits.These include lower all-cause,cardiovascular,and cancer mortality.From a morbidity perspective,being fit is associated with a decreased risk of coronary heart disease,stroke,type 2 diabetes,metabolic syndrome,hypertension,certain cancers,depression,and memory loss.We will discuss many of these studies in the following text.

7 心肺健康與冠狀動(dòng)脈危險(xiǎn)因素

20世紀(jì)70年代早期，有一些證據(jù)表明身體活動(dòng)對(duì)冠心病具有保護(hù)作用，但其機(jī)制在很大程度上是未知的。庫(kù)珀博士是研究平均年齡為45歲的3 000名男性（他們?cè)?970—1974年間進(jìn)行了檢查[4]）客觀(guān)測(cè)量的心肺功能（Cardiorespiratory fitness，CRF）與冠狀動(dòng)脈危險(xiǎn)因素之間關(guān)聯(lián)的第一人。根據(jù)年齡和最大跑臺(tái)運(yùn)動(dòng)測(cè)試表現(xiàn)，將男性CRF按五分位數(shù)（Quintile）分為5類(lèi)，在CRF五分位數(shù)人群上分組檢查總膽固醇、甘油三酯、葡萄糖、血壓、體脂百分比和靜息心率。觀(guān)察到CRF與所有這些變量之間呈負(fù)相關(guān)。即使將CRF的最低五分位數(shù)與下一個(gè)最高五分位數(shù)進(jìn)行比較，也可以顯示出這種關(guān)系。這是第一項(xiàng)報(bào)告客觀(guān)測(cè)量的心肺功能與冠狀動(dòng)脈危險(xiǎn)因素關(guān)聯(lián)性的研究，也是ACLS的第一篇論文。

7 Card iorespiratory Fitnessand Coronary Risk Factors

By the early 1970’s there was some evidence that physical activity was protective against coronary heart disease,but the mechanisms were largely unknown.Dr.Kenneth Cooper was the first to examine the association between objectively measured cardiorespiratory fitness(CRF)and coronary risk factors in 3 000 men with a mean age 45 years who were examined between 1970 and 1974[4].Men were divided into 5 categories(quintiles)of CRF based on their age and maximal treadmill exercise test performance.Total cholesterol,triglycerides,glucose,blood pressure,percent body fat,and resting heart rate were examined across CRF quintiles.An inverse association between CRF and all of those variables was observed.This re lationship was shown for most variables even when comparing the lowest quintile of CRF with the next highest quintile.This was the first study to report on these associations,and also represents the first ACLS paper.

8 CRF和全因死亡率

1989年，庫(kù)珀研究所和庫(kù)珀診所的研究人員發(fā)表了被認(rèn)為具有里程碑意義的CCLS論文[5]。該論文發(fā)表在美國(guó)醫(yī)學(xué)會(huì)雜志（JAMA）上，報(bào)告了13 344名平均年齡為45歲的男性和女性在基線(xiàn)綜合預(yù)防性檢查后接受了超過(guò)8年的隨訪(fǎng)。根據(jù)他們的最大跑臺(tái)運(yùn)動(dòng)測(cè)試表現(xiàn)，以及年齡和性別，對(duì)每個(gè)客戶(hù)的CRF按五分位數(shù)進(jìn)行分類(lèi)，Quintile1代表低水平CRF，Quintile2-3和Quintile4-5分別代表中等水平CRF和高水平CRF。在隨訪(fǎng)期間，有283名全因死亡。在隨訪(fǎng)期間發(fā)現(xiàn)基線(xiàn)CRF與死亡風(fēng)險(xiǎn)之間存在顯著的負(fù)相關(guān)，換句話(huà)說(shuō)，與基線(xiàn)時(shí)低CRF的男性和女性相比，在基線(xiàn)時(shí)中高水平CRF的男性和女性在隨訪(fǎng)期間死亡的可能性大大降低。當(dāng)對(duì)Quintile1和Quintile2進(jìn)行比較時(shí)，顯示出現(xiàn)風(fēng)險(xiǎn)差異最大，這是第一項(xiàng)明確證明CRF是男性和女性全因死亡率的重要且獨(dú)立預(yù)測(cè)因子的研究。

8 CRF and all-cause Mortality

In 1989,Cooper Institute and Cooper Clinic researchers published what is considered the landmark CCLS paper[5].Published in the Journal of the Ameri can Medical Association,this study reported on 13 344 men and women with an average age of 45 years who were followed for just over 8 years following their baseline comprehensive preventive exam.Based on their maximal treadmill exercise test performance,as well as age and sex,each patient was placed into quintiles of CRF.Quintile 1 represents low CRF,while quintiles 2-3 and 4-5 represent moderate and high CRF,respectively.There were 283 all-cause deaths during the follow-up period.A strong inverse relationship between baseline CRF and risk of death was found during follow-up.In other words,men and women who were moderately-to-highly fit at baseline were substantially less likely to die during the follow-up when compared to men and women who were low fit at baseline.The greatest reduction in risk was seen when comparing the lowest fit group (quintile 1)with the next lowest fit group(quintile 2).This was the first study to definitively prove that CRF is a significant and independent predictor of all-cause mortality in men and women.

9 CRF，冠狀動(dòng)脈鈣化和心血管事件

近年來(lái)，冠狀動(dòng)脈鈣化（Coronary artery calcium，CAC）評(píng)分一直是研究者預(yù)測(cè)未來(lái)心血管疾病發(fā)生風(fēng)險(xiǎn)的主要研究課題。雖然CRF和CAC分別對(duì)心血管疾病發(fā)生風(fēng)險(xiǎn)預(yù)測(cè)有很大貢獻(xiàn)，但令人驚訝的是，人們對(duì)CRF如何影響不同類(lèi)別CAC的心血管疾病風(fēng)險(xiǎn)仍知之甚少?？紤]到這一點(diǎn)，1998年至2007年間檢測(cè)的8 425名年齡在30～80歲之間的健康庫(kù)珀診所男性樣本中檢查這些關(guān)系[6]，對(duì)他們的綜合檢測(cè)包括測(cè)量CRF的最大跑臺(tái)運(yùn)動(dòng)測(cè)試、確定CAC評(píng)分的CT掃描，以及傳統(tǒng)心血管疾病危險(xiǎn)因素的仔細(xì)測(cè)量。跟蹤樣本時(shí)間平均為8.4年，在此期間發(fā)生了383個(gè)致命和非致命的心血管疾病發(fā)生案列。CAC評(píng)分為0的男性心血管疾病發(fā)生風(fēng)險(xiǎn)發(fā)生率非常低 （1 000人每年發(fā)生1.3次事件），而CAC評(píng)分≥400的男性心血管疾病發(fā)生風(fēng)險(xiǎn)發(fā)生率則大大增高（1 000人每年發(fā)生18.9次事件）。根據(jù)以前的研究，這一結(jié)果是預(yù)料之中的。一項(xiàng)包括CRF的新的研究結(jié)果如圖2所示，圖2顯示了基線(xiàn)檢查后15年內(nèi)4個(gè)CAC類(lèi)別在不同CRF水平的心血管疾病發(fā)生風(fēng)險(xiǎn)，最大年齡至70歲。在每個(gè)CAC類(lèi)別中，心血管疾病發(fā)生風(fēng)險(xiǎn)隨著CRF水平的增加而降低。在CAC評(píng)分較高的男性中，CRF風(fēng)險(xiǎn)降低更為明顯。如圖2所示，CAC評(píng)分為0的非常健康的男性疾病發(fā)生風(fēng)險(xiǎn)最低，而CAC評(píng)分≥400的非常不健康的男性疾病發(fā)生風(fēng)險(xiǎn)最高。需要強(qiáng)調(diào)的是，較高水平的CRF可在所有4種CAC類(lèi)別中對(duì)心血管疾病發(fā)生風(fēng)險(xiǎn)提供一定程度的保護(hù)。

圖2 基線(xiàn)檢查后15年內(nèi)4個(gè)CAC類(lèi)別在不同CRF水平的心血管疾病發(fā)生風(fēng)險(xiǎn)Figure 2 Risk of CVD Events by Age 70 by CAC Score

9 CRF,Coronary Artery Calcium,and Cardiovascular Events

In recent years,coronary artery calcium(CAC)score has been a major topic of interest with regard to predicting future cardiovascular events.Although CRF and CAC each contribute strongly to prediction of these events,surprisingly little is known regarding how CRF impacts cardiovascular disease risk across different categories of CAC.With this in mind,we sought to examine these relationships in a sample of 8 425 generally healthy Cooper Clinic men between the ages of 30 and 80 who were examined between 1998 and 2007[6].Their comprehensive exam included a maximal treadmill exercise test to measure CRF,a CT scan to determine CAC score,as well as careful measurement of traditional cardiovascular disease risk factors.The sample was followed for an average of 8.4 years,during which time 383 fatal and non-fatal cardiovascular events occurred.While men with CAC scores of 0 had a very low rate of cardiovascular events(1.3 events per 1 000 person-years),men with CAC scores of＞400 had a much higher rate(18.9 events per 1 000 person-years).Based on previous studies,this finding was expected.A more novel finding is shown in the Figure below.The Figure shows the risk of cardiovascular events up to the age of 70 across CRF level in the 4 CAC categories over a 15 year period following the baseline exam.Within each CAC category,the risk of cardiovascular events decreased across increasing levels of CRF.The decrease in risk across CRF was more pronounced among men with higher CAC scores.As the Figure shows,the lowest risk was seen in very highly fit men with CAC scores of 0,while the highest risk was seen in very low fit men with CAC scores＞400.What is important to reinforce is that higher levels of CRF provide some degree of protection against cardiovascular events in all 4 CAC categories.

10 中年CRF與慢性病的發(fā)展

年齡的增長(zhǎng)與心臟病和糖尿病等幾種慢性疾病的發(fā)展密切相關(guān)。2012年，我們檢查了中年CRF與老年非致命性慢性病發(fā)展之間的關(guān)系[7]。研究對(duì)象由來(lái)自庫(kù)珀診所的18 670名看起來(lái)健康的男性和女性組成，平均年齡為49歲，他們接受了基線(xiàn)預(yù)防性檢查，并確定可以在1999—2009年期間接受醫(yī)療保險(xiǎn)，共研究了 8種慢性病 （Chronic conditions，CC）：充血性心力衰竭、缺血性心臟病、中風(fēng)、糖尿病、慢性阻塞性肺病、慢性腎病、阿爾茨海默病和結(jié)腸癌或肺癌。將受試者按CRF的五分位數(shù)分類(lèi)，從基線(xiàn)檢查開(kāi)始的平均隨訪(fǎng)時(shí)間為26年。將最低CRF五分位數(shù)的男性與CRF最高五分位數(shù)的男性進(jìn)行比較，未來(lái)CC的發(fā)生比率分別為每年每10人出現(xiàn)了2.82和每年每10人出現(xiàn)了1.56/10人。將最低CRF五分位數(shù)的女性與最高CRF五分位數(shù)的女性進(jìn)行比較，未來(lái)CC的比率分別為每年2.01/10人和1.14/10人。因此，中年時(shí)較高水平的CRF與晚年患慢性病的風(fēng)險(xiǎn)降低顯著相關(guān)，見(jiàn)圖3。

圖3 按CRF水平高低分為5組的18 670名健康中年男性和女性的慢性疾病發(fā)生率Figure 3 Rate of Chronic Conditions by Midlife CRF Measurement in 18 670 Healthy Men and Women

10 Midlife CRF and Development of Chronic Conditions

Older age is strongly associated with development of several chronic conditions such as heart disease and diabetes.In 2012,we examined the association of midlife CRF and the development of non-fatal chronic conditions in older age[7].The sample consisted of 18 670 apparently healthy Cooper Clinic men and women with an average age of 49 years,who received a baseline preventive exam and survived long enough to receive Medicare coverage from 1999-2009.Eight chronic conditions(CCs)were studied:congestive heart failure,ischemic heart disease,stroke,diabetes mellitus,chronic obstructive pulmonary disease,chronic kidney disease,Alzheimer’s disease,and colon or lung cancer.Subjects were placed into quintiles of CRF as previously described.The average length of follow-up from the time of the baseline exam was 26 years.When comparing men in the lowest CRF quintile to men in the high-est CRF quintile,the rate of future CC’s was 2.82 versus 1.56 per 10 person-years,respectively.When comparing women in the lowest CRF quintile to women in the highest CRF quintile,the rate of future CC’s was 2.01 versus 1.14 per 10 person-years,respectively.Thus,higher levels of CRF at midlife were significantly associated with a reduced risk of developing chronic conditions later in life.See Figure below.

11 中年CRF與全因癡呆癥

隨著美國(guó)人口平均年齡的持續(xù)增加，全因癡呆癥已成為老年人的主要健康問(wèn)題。因此，庫(kù)珀診所檢查了中年CRF與全因癡呆未來(lái)發(fā)展風(fēng)險(xiǎn)之間的關(guān)聯(lián)，這一點(diǎn)已經(jīng)過(guò)醫(yī)療保險(xiǎn)數(shù)據(jù)驗(yàn)證[8]。研究對(duì)象為包括19 458名健康男性和女性，平均年齡為49歲。將受試者按CRF的五分位數(shù)分類(lèi)，在25年的隨訪(fǎng)期間，發(fā)生了1 659例全因癡呆病例。CRF最高分位數(shù)的受試者發(fā)生全因癡呆的可能性比最低五分位數(shù)的受試者低36%。重要的是，這是第一項(xiàng)顯示中年CRF與未來(lái)全因癡呆風(fēng)險(xiǎn)之間顯著相關(guān)的研究。

11 Midlife CRF and all-cause Dementia

As the average age of the U.S.population continues to increase,all-cause dementia has become a major health issue among older adults.Accordingly,we examined the association between midlife CRF and the future risk of developing of all-cause dementia as veri fied by Medicare data[8].The sample included 19 458 healthy Cooper Clinic men and women with a mean age of 49 years.Subjects were placed into quintiles of CRF as described previously.During a 25 year follow-up period,1 659 cases of all-cause dementia occurred.There was a decreased risk of dementia across quintiles of CRF,with subjects in the highest CRF quintile 36%less likely to develop all-cause dementia than subjects in the lowest quintile.Importantly,this was the first study to show a significant association between midlife CRF and the future risk of all-cause dementia.

12 中年健身和慢性腎病

慢性腎?。–hronic kidney disease，CKD）在老年人群和糖尿病客戶(hù)中很常見(jiàn)。使用CCLS和醫(yī)療保險(xiǎn)數(shù)據(jù)，我們檢查了中年CRF與CKD發(fā)生風(fēng)險(xiǎn)的關(guān)系[9]。研究對(duì)象包括17 979名健康男性和女性，平均年齡為50歲，在1971年至2009年期間接受檢查，并在1999—2009年接受醫(yī)療保險(xiǎn)。在每年116 973人的醫(yī)療保險(xiǎn)追蹤中共發(fā)生2 022例CKD，與較低健康水平者相比，中等水平和高水平CRF研究對(duì)象發(fā)生CKD的可能性分別低24%和34%，即使在隨訪(fǎng)期間患上糖尿病的客戶(hù)中，CRF每增加1 MET，CKD的風(fēng)險(xiǎn)也會(huì)降低6%。

12 Midlife Fitness and Chronic Kidney Disease

Chronic kidney disease(CKD)is common among the older population as well as those with diabetes mellitus.Using CCLS as well as Medicare data,we examined the association of midlife CRF and subsequent risk of CKD[9].The sample consisted of 17 979 apparently healthy men and women with a mean age of 50 years,who were examined between 1971 and 2009,who also r eceived Medicare coverage from 1999 to 2009.A total of 2022 cases of incident CKD occurred during 116 973 person-years of Medicare follow-up.Individuals with moderate and high CRF were 24%and 34%less likely,respectively,to develop CKD when compared to those who were low fit.Even among those who developed diabetes mellitus during follow-up,the risk of CKD was reduced by 6%per 1-MET increment in CRF.

13 中年CRF與中風(fēng)風(fēng)險(xiǎn)

在美國(guó)，中風(fēng)是造成長(zhǎng)期殘疾的主要原因，也是導(dǎo)致死亡的主要原因之一。盡管低水平的CRF已成為中風(fēng)的一個(gè)強(qiáng)大且獨(dú)立的危險(xiǎn)因素[10]，但尚不清楚這種相關(guān)性在何種程度上可通過(guò)糖尿病、高血壓和心房顫動(dòng)等中風(fēng)危險(xiǎn)因素的發(fā)展來(lái)解釋。庫(kù)珀診所檢查了中年CRF與65歲以后中風(fēng)風(fēng)險(xiǎn)之間的關(guān)系，并排除上述風(fēng)險(xiǎn)因素的影響[11]，共有19 815名在基線(xiàn)時(shí)平均年齡為50歲的庫(kù)珀診所客戶(hù)參與了該研究。所有人看起來(lái)都很健康，且在檢驗(yàn)時(shí)中風(fēng)風(fēng)險(xiǎn)相對(duì)較低?；谒麄兊呐芘_(tái)運(yùn)動(dòng)測(cè)試表現(xiàn)，將每個(gè)個(gè)體劃分為低、中或高CRF類(lèi)別。共有每年129 436人的醫(yī)療保險(xiǎn)隨訪(fǎng)數(shù)據(jù)，在此期間發(fā)生了808例中風(fēng)住院治療案例。重要的是，在分析中還仔細(xì)考慮了在臨床檢查時(shí)可能未檢測(cè)的中風(fēng)時(shí)的高血壓、糖尿病或心房顫動(dòng)的數(shù)據(jù)。使用低CRF組作為對(duì)照組，在醫(yī)療保險(xiǎn)隨訪(fǎng)期間，中年時(shí)期中等水平CRF和高水平CRF研究對(duì)象因中風(fēng)住院治療的可能性分別為24%和37%。重要的是，這些數(shù)字是在考慮了基線(xiàn)時(shí)出現(xiàn)的中風(fēng)危險(xiǎn)因素以及中風(fēng)診斷時(shí)出現(xiàn)的中風(fēng)危險(xiǎn)因素后確定的。因此，無(wú)論在研究期間的任何時(shí)間是否存在高血壓、糖尿病或心房顫動(dòng)，CRF仍然是中風(fēng)住院風(fēng)險(xiǎn)的很有效的預(yù)測(cè)因子。

13 Midlife CRF and Risk of Stroke

Stroke is the leading cause of long-term disability in the U.S.,and is also among the leading causes of death.Although low levels of CRF have emerged as a strong and independent risk factor for stroke[10],it is not known to what extent this association is explained by development of stroke risk factors such as diabetes,hypertension,and atrial fibrillation.We examined the association of midlife CRF and risk of stroke after the age of 65 years,independent of these risk factors[11].A total of 19 815 Cooper Clinic patients with an average age of 50 years at baseline participated in the study.All were apparently healthy,with a relatively low risk of stroke at the time of their exam.Based on their treadmill test performance,each individual was placed into low,moderate,or high CRF categories as previously described.There were a total of 129 436 person-years of Medicare follow-up data,during which time 808 stroke hospitalizations occurred.Importantly,data regarding the presence of hypertension,diabetes,or atrial fibrillation at the time of the stroke that may not have been present at the time of the Clinic exam was also carefully considered in the analyses.Using the low CRF group as the referent,patients with moderate and high CRF at midlife were 24%and 37%less likely to be hospitalized for stroke,respectively,during the period of Medicare follow-up.Importantly,these numbers were determined after taking baseline stroke risk factors into account,as well as stroke risk factors that were present at the time the stroke was diagnosed.Thus,independently of whether or not hypertension,diabetes,or atrial fibrillation was present at any time during the study,CRF remained a strong predictor of stroke hospitalization risk.

14 中年CRF與癌癥發(fā)病率和癌癥存活率

癌癥是美國(guó)第二大死亡原因。CRF與癌癥以及癌癥診斷后的存活率在很大程度上是未知的。庫(kù)珀診所試圖通過(guò)利用CCLS和醫(yī)療保險(xiǎn)數(shù)據(jù)來(lái)檢查中年CRF與肺癌、前列腺癌和結(jié)直腸癌之間的關(guān)系，以及中年CRF與癌癥診斷后存活率的關(guān)系[12]。1971—2009年期間，庫(kù)珀診所共檢查了13 949名男性，平均年齡為49歲。男性按CRF水平分為低、中、高組。與低水平CRF的男性相比，高水平CRF的男性罹患肺癌和結(jié)直腸癌的可能性分別低55%和44%。然而，CRF較高的男性患前列腺癌的可能性比較低健康程度男性高22%。CRF每增加1 MET，肺癌和結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)分別降低17%和9%。我們推測(cè)，較高健康程度男性的前列腺癌發(fā)病率較高的原因可能是由于與較低健康程度男性相比，該組中有著更頻繁的醫(yī)療保健篩查。在醫(yī)療保險(xiǎn)年齡范圍內(nèi)被診斷患有癌癥的男性中，觀(guān)察到與較低健康程度男性相比，較高健康程度的男性癌癥死亡率降低了32%，而且心血管疾病死亡率降低了68%。

14 Midlife CRF,Cancer Incidence,and Cancer Survival

Cancer is the second leading cause of death in the U.S.The association between CRF and incident cancer,as well as survival following a diagnosis of cancer is largely unknown.We sought to examine the association of midlife CRF and incident lung,prostate,and colorectal cancer,as well as the association of midlife CRF with survival following a cancer diagnosis by utilizing CCLS and Medicare data[12].A total of 13 949 men with a mean age of 49 years were examined at the Cooper Clinic between 1971 and 2009.Men were placed into low,moderate,and high CRF categories as previously described.When compared to men with low CRF,men with high CRF were 55%and 44%less likely to develop lung and colorectal cancer,respectively.However,men with high CRF were 22%more likely to develop prostate cancer than low fit men.Each 1-MET increase in CRF was associated with a 17%and 9%reduction in risk of incident lung and colorectal cancer,respectively.We speculate that the reason for the higher incidence of prostate cancer in high fit men may be due to more frequent health care screening among this group as compared to low fit men.Among men diagnosed with cancer at Medicare age,we observed a 32%reduction in cancer mortality,and a 68%reduction on cardiovascular disease mortality in high fit men as compared to low fit men.

15 中年CRF與心力衰竭住院治療

心力衰竭（Heart failure，HF）是美國(guó)65歲及以上人群住院治療的最常見(jiàn)原因之一。通過(guò)結(jié)合CCLS數(shù)據(jù)與醫(yī)療保險(xiǎn)數(shù)據(jù)，庫(kù)珀診所在19 485名男性和女性中檢查了中年CRF與因HF住院產(chǎn)生的CRF變化之間的關(guān)系[13]。在對(duì)基線(xiàn)檢查的傳統(tǒng)HF風(fēng)險(xiǎn)因素進(jìn)行調(diào)整后，較高水平CRF與HF住院風(fēng)險(xiǎn)的降低有關(guān)，每增加1 MET的跑臺(tái)運(yùn)動(dòng)測(cè)試成績(jī)，HF住院風(fēng)險(xiǎn)降低18%。一部分客戶(hù)（n=8 683）接受了第二次檢查，距基線(xiàn)檢查的平均時(shí)間為4.2年。在基線(xiàn)檢查時(shí)健康（Quintile2-5）且持續(xù)保持健康的個(gè)體后續(xù)HF住院的風(fēng)險(xiǎn)最低。相反，在基線(xiàn)檢查時(shí)不健康（Quintile1）且仍持續(xù)不健康的個(gè)體HF住院的風(fēng)險(xiǎn)最高。基線(xiàn)時(shí)不健康但進(jìn)行隨訪(fǎng)檢查時(shí)恢復(fù)健康的個(gè)體有中等程度的HF住院治療風(fēng)險(xiǎn)。

15 Midlife CRF and Heart Failure Hospitalization

Heart failure(HF)is the most common reason for hospitalization in the U.S.among individuals ages 65 and older.By linking CCLS data with Medicare data,we examined the associations of midlife CRF and change in midlife CRF with HF hospitalizations in a group of 19 485 men and women[13].Following adjust ment for traditional HF risk factors at the baseline examination,higher CRF was associated with an 18%lower risk for HF hospitalization per 1-MET increment in treadmill test performance.A subset of patients(n=8,683)underwent a second exam,with a mean period of 4.2 years after the baseline exam.Individuals who were fit as baseline (Quintiles 2-5)and remained fit had the lowest risk for subsequent HF hospitalization.Conversely,individuals who were unfit at baseline (Quintile 1)and remained unfit had the highest risk for HF hospitalization.Individuals who were unfit as baseline,but fit at the follow-up exam had an intermediate risk for HF hospitalization.

16 CRF與肥胖和心力衰竭死亡率

雖然已有文獻(xiàn)報(bào)道了身體活動(dòng)與心力衰竭之間的關(guān)聯(lián)，但迄今為止沒(méi)有研究檢查過(guò)客觀(guān)測(cè)量的CRF與心力衰竭死亡率之間的關(guān)系。庫(kù)珀診所追蹤了44 674名庫(kù)珀診所男性，平均年齡為19.8歲[14]。在基線(xiàn)檢查時(shí)，所有男性看起來(lái)都很健康，按CRF水平分為低、中、高組，且基于標(biāo)準(zhǔn)BMI類(lèi)別被分類(lèi)為正常體重、超重或肥胖。在隨訪(fǎng)期間，有153名男子死于HF，與高CRF男性相比，中等和低CRF男性因HF死亡的可能性分別高1.63倍和3.97倍。與正常體重男性相比，超重和肥胖男性因HF死亡的可能性分別高1.56和3.71倍。在正常體重和超重類(lèi)別中，中高CRF男性死于HF的可能性大大低于低CRF男性。此外，在具有相同數(shù)量HF風(fēng)險(xiǎn)因素的男性中，中高CRF男性死于HF的可能性大大低于低CRF男性。例如，對(duì)于有1個(gè)HF危險(xiǎn)因素的男性來(lái)說(shuō)，低CRF男性死于HF的可能性是中高CRF男性的4倍。

16 CRF,Adiposity,and Heart Failure Mortality

While associations between physical activity and heart failure have been reported in the literature,no study to date had examined the association of objectively measured CRF and heart failure mortality.We followed 44 674 Cooper Clinic men over an average period of 19.8 years[14].At baseline,all of the men were ap parently healthy.Participants were assigned to low,moderate,and high CRF categories as described previously,and were classified as normal weight,overweight,or obese based on standard body mass index(BMI)categories.During the follow-up period,153 men died from HF.Compared with high fit men,moderate and low fit men were 1.63 and 3.97 times more likely to die from HF,respectively.Compared to normal weight men,overweight and obese men were 1.56 and 3.71 times more likely to die from HF,respectively.Within the normal weight and overweight categories,fit men were substantially less likely to die from HF than unfit men.Additionally,among men with the same number of risk factors for HF,fit men were substantially less likely to die from HF than unfit men.For example,among men who had 1 risk factor for HF,unfit men were about 4 times more likely to die from HF than fit men.

17 健康行為和長(zhǎng)期醫(yī)療保健費(fèi)用

17.1 老年CRF與醫(yī)療保健費(fèi)用

雖然普遍認(rèn)為中年心血管危險(xiǎn)因素與以后的醫(yī)療保健成本相關(guān)，但與這些風(fēng)險(xiǎn)因素?zé)o關(guān)的CRF對(duì)醫(yī)療保健成本影響的數(shù)據(jù)仍舊匱乏。研究了19 571名健康男性和女性，平均年齡為49歲，他們?cè)趲?kù)珀診所接受檢查，隨后在1999—2009年期間接受了醫(yī)療保險(xiǎn)[15]，按CRF水平分為低、中、高組。醫(yī)療保險(xiǎn)的平均隨訪(fǎng)時(shí)間為6.5年，共計(jì)每年126 388人的數(shù)據(jù)。當(dāng)比較中年高水平CRF和低水平CRF的參與者時(shí)，男性（分別為7 569美元、12 811美元）和女性（分別為6 065美元、10 019美元）的平均年度醫(yī)療保健費(fèi)用顯著降低。根據(jù)心血管危險(xiǎn)因素進(jìn)行調(diào)整后，CRF每增加1 MET，男性和女性的平均年度醫(yī)療保健費(fèi)用分別降低6.8%和6.7%。

17.2 簡(jiǎn)單生活7要素（Life's Simple 7）與長(zhǎng)期醫(yī)療保健費(fèi)用

美國(guó)心臟協(xié)會(huì)開(kāi)發(fā)了“Life's Simple 7”，囊括了與心血管健康密切相關(guān)的行為和因素[16]。包括飲食、身體活動(dòng)、吸煙、體重指數(shù)、血液膽固醇、血糖和靜息血壓。每個(gè)要素分為較差、中等或理想3個(gè)水平。把7要素達(dá)到理想水平的狀態(tài)定義為理想的心血管健康。為了評(píng)估這7個(gè)要素的經(jīng)濟(jì)影響，對(duì)1999—2009年期間入選醫(yī)療保險(xiǎn)的4 906名庫(kù)珀診所平均年齡為56的中年男性和女性樣本進(jìn)行了評(píng)估[17]。根據(jù)他們的基線(xiàn)檢查結(jié)果，將他們分為3個(gè)等級(jí)：（1）不利，具有0～2項(xiàng)理想心血管健康特征；（2）中等，具有3～4 項(xiàng)理想心血管健康特征；（3）有利，具有 5～7 項(xiàng)理想心血管健康特征。不到1%的參與者具有所有7個(gè)理想特征，而14.8%的男性和30.1%的女性被劃分為有利組。不利組的年均非心血管疾病醫(yī)療保險(xiǎn)費(fèi)用為5 058美元，而有利組為3 883美元。年均心血管疾病費(fèi)用中也有相同趨勢(shì) （不利組和有力組分別為1 344美元及778美元）。因此，在中年期間具有更多數(shù)量的理想心血管健康特征與晚年的醫(yī)療保健成本成顯著負(fù)相關(guān)。

17 Healthy Behaviors and Long-Term Health Care Costs

17.1 CRF and Health Care Costs in Later Life

While it is accepted that cardiovascular risk factor burden in middle age is associated with health care costs later in life,data regarding the effect of CRF on health care costs independent of these risk factors is lacking.We studied 19 571 apparently healthy men and women with an average age of 49 years who were examined at Cooper Clinic and subsequently received Medicare coverage from 1999 to 2009[15].CRF was categorized as low,moderate,and high as previously described.There was a mean Medicare follow-up of 6.5 years,resulting in 126 388 person-years ofdata.When comparing participantswith high CRF at midlife to those with low CRF,average annual health care costs were significantly lower in men($7 569 vs.$12 811)and women($6 065 vs.$10 019).When adjusted for cardiovascular risk factors,average annual health care costs were 6.8%and 6.7%lower in men and women,respectively,per 1-MET increment in CRF.

17.2 Life’s Simple 7 and Long-Term Health Care Costs

The American Heart Association developed “Life′s Simple 7”which includes behaviors and factors that strongly relate to cardiovascular health[16].These in clude healthy diet,physical activity,smoking,body mass index,blood cholesterol,blood glucose,and resting blood pressure.Each component is categorized as either poor,intermediate,or ideal.Ideal cardiovascular health is defined by having ideal levels of each of the 7 components.In order to evaluate the economic impact of these 7 factors,a sample of 4 906 Cooper Clinic middle-aged men and women with a mean baseline age of 56 who were enrolled in Medicare between 1999 and 2009 were evaluated[17].Subjects were categorized into one ofthree cardiovascular health profile groups according to their baseline exam:1)Unfavorable(0-2 ideal cardiovascular health characteristics)2)Intermediate (3-4 ideal cardiovascular health characteristics) 3)Favorable(5-7 ideal cardiovascular health characteristics).Less than 1%of participants had all 7 ideal characteristics,while 14.8%of men and 30.1%of women scored in the Favorable group.The mean annual non-cardiovascular disease Medicare costs in the Unfavorable group was$5 058 versus$3 883 in the Favorable group.A similar trend was seen for mean annual cardiovascular disease costs($1 344 versus$778 in Unfavorable vs.Favorable groups,respectively).Thus,having a greater number of ideal cardiovascular health components in middle-age is associated with significantly lower Medicare costs in later life.

18 CRF與代謝綜合征的發(fā)生率

代謝綜合征（Metabolic syndrome，MetSyn）是一種常見(jiàn)病癥，具有以下至少3項(xiàng)表現(xiàn)：高腰圍、低HDL膽固醇、血液甘油三酯水平升高、血糖水平升高和靜息血壓升高?；加蠱etSyn的個(gè)體全因和心血管死亡的風(fēng)險(xiǎn)增加。CCLS以前的研究表明，中高CRF女性與低CRF女性MetSyn的發(fā)生率更低[18]。該研究的目的是確定健康人的基線(xiàn)CRF是否是MetSyn的預(yù)測(cè)因子。1979—2003年期間，共有9 007名男性和1 491名女性在基線(xiàn)檢查時(shí)沒(méi)有MetSyn；他們的平均年齡是44歲，按CRF水平劃分為低、中和高3組。在平均5.7年的隨訪(fǎng)期間，1 346名男性和56名女性患上了MetSyn。與低CRF男性相比，中高CRF水平男性罹患MetSyn的可能性分別為26%和53%。與低CRF女性相比，中高CRF水平女性發(fā)展MetSyn的可能性分別為20%和63%[19]。這項(xiàng)研究首次表明，低水平CRF是男性和女性MetSyn的有效因子，因此，在許多情況下，可以通過(guò)簡(jiǎn)單地實(shí)現(xiàn)中等至高水平的CRF來(lái)預(yù)防MetSyn。

18 CRF and Incidence of Metabolic Syndrome

Metabolic syndrome(MetSyn)is a common condition characterized by any three or more of the following:high waist circumference,low HDL cholesterol,elevated blood triglyceride level,elevated blood glucose level,and elevated resting blood pressure.Individuals with MetSyn are at increased risk for all-cause and cardiovascular mortality.Previous work in the CCLS had shown that MetSyn was much less common among fit women than unfit women[18].The purpose of this study was to determine whether baseline CRF in healthy persons was a predictor of incident MetSyn.A total of 9 007 men and 1 491 women who did not have MetSyn at baseline were evaluated between 1979 and 2003;their average age was 44 years.Patients were placed into categories of low,moderate,and high CRF as previously described.During an average follow-up period of 5.7 years,1346 men and 56 women developed MetSyn.When compared to low fit men,moderate and high fit men were 26%and 53%less likely to develop MetSyn,respectively.When compared to low fit women,moderate and high fit women were 20%and 63%less likely to develop MetSyn,respectively[19].This study was the first to show that a low baseline level of CRF is a strong predictor of incident MetSyn in both men and women.Thus,in many cases MetSyn might be prevented by simply achieving a moderate to high level of CRF.

19 CRF，肥胖與死亡率

雖然體重狀態(tài)和CRF都是重要的健康指標(biāo)，但這是第一項(xiàng)旨在比較CRF與體重狀態(tài)在死亡風(fēng)險(xiǎn)方面重要性的CCLS研究[20]。將25 389名庫(kù)珀診所男性樣本分為低、中、高3種CRF類(lèi)別，同時(shí)還被分為正常體重、超重和肥胖的BMI類(lèi)別，以研究上述兩因素與死亡風(fēng)險(xiǎn)之間的關(guān)系。在平均8.5年的隨訪(fǎng)期間共有673人死亡。在每個(gè)BMI類(lèi)別中，在CRF水平較高的情況下，全因死亡率的風(fēng)險(xiǎn)顯著降低。因此，即使在超重和肥胖男性中，較高水平的CRF也可以降低死亡率。這是第一項(xiàng)顯示CRF與死亡率相關(guān)性高于BMI的研究。因此，在所有BMI類(lèi)別中都可以看到具有中高水平CRF的益處。這項(xiàng)重要的研究為許多未來(lái)探討 “健康與肥胖”問(wèn)題的CCLS研究奠定了基礎(chǔ)。

19 Fitness,Fatness,and Mortality

While body weight status and CRF are each important health markers,this was the first CCLS study to examine the relative importance of CRF versus body weight status with regard to mortality risk[20].A sample of 25 389 Cooper Clinic men was divided into CRF categories of low,moderate,and high based as previously described.They were also divided into body mass index (BMI)categories of normal weight,overweight,and obese based on criteria at that time.All possible combinations of CRF and BMI were made in order to examine their relative contribution to mortality risk.A total of 673 deaths occurred during an average 8.5 year follow-up period.Within each category of BMI,there was a significantly lower risk of all-cause mortality across increasing levels of CRF.Thus,even in overweight and obese men,higher levels of CRF were protective against mortality.This was the first study to show that CRF is more strongly associated with mortality than BMI.Thus,the benefits of having a moderate to high level of CRF are seen across all BMI categories.This important study helped set the stage for many future CCLS studies examining the ‘fitness versus fatness’issue.

20 CRF與心血管風(fēng)險(xiǎn)分類(lèi)

心血管疾?。–ardiovascular disease，CVD）是導(dǎo)致居住在生活水平較高的國(guó)家的成年人死亡的主要原因之一。CVD的傳統(tǒng)影響因素包括血膽固醇水平升高、高血壓、吸煙、糖尿病、年齡、家族史、不活動(dòng)和肥胖。在過(guò)去的30年中，低水平的CRF已經(jīng)成為一個(gè)非常強(qiáng)大和獨(dú)立的CVD風(fēng)險(xiǎn)因素。盡管已經(jīng)開(kāi)發(fā)出許多預(yù)測(cè)未來(lái)心血管疾病風(fēng)險(xiǎn)的公式，但這些公式都沒(méi)有把CRF水平包括在共識(shí)的風(fēng)險(xiǎn)因素中。事實(shí)上，CRF通常是在體檢期間非常規(guī)測(cè)量的唯一主要風(fēng)險(xiǎn)因素。本研究的目的是確定當(dāng)加入傳統(tǒng)危險(xiǎn)因素時(shí)，CRF在多大程度上能降低CVD的風(fēng)險(xiǎn)[21]。研究共有66 371名庫(kù)珀診所男性和女性接受了全面的基線(xiàn)檢查，按CRF水平進(jìn)行分類(lèi)。樣本平均跟蹤時(shí)間為16年，在此期間CVD導(dǎo)致1 621例死亡。正如預(yù)期的那樣，男性和女性的CRF水平與CVD死亡風(fēng)險(xiǎn)降低有關(guān)。接下來(lái)，使用傳統(tǒng)的風(fēng)險(xiǎn)因素，如年齡、靜息血壓、血膽固醇水平、糖尿病和吸煙，來(lái)預(yù)測(cè)樣本中CVD死亡的風(fēng)險(xiǎn)。當(dāng)CRF被添加到預(yù)測(cè)公式中時(shí)，方程的準(zhǔn)確性得到顯著改善。換句話(huà)說(shuō)，了解客戶(hù)的CRF水平可以讓醫(yī)生更好地評(píng)價(jià)他們的CVD發(fā)生風(fēng)險(xiǎn)。該研究與許多其他CCLS論文一起，有助于建議美國(guó)心臟協(xié)會(huì)將心肺健康測(cè)量作為一個(gè)評(píng)價(jià)CVD發(fā)生風(fēng)險(xiǎn)的重要標(biāo)志[22]。

20 Cardiovascular Risk Classification and CRF

Cardiovascular disease(CVD)is the leading cause of death among adults residing in countries with a rela tively high standard of living.Traditional risk factors for CVD include elevated blood cholesterol level,hypertension,smoking,diabetes,age,family history,inactivity,and obesity.Over the past three decades,a low level of CRF has emerged as a very powerful and independent risk factor as well.Although equations for predicting risk of future cardiovascular disease have been developed,these equations have historically excluded CRF level as a risk factor.In fact,CRF is often the only major risk factor that is not routinely measured during physical examinations.The purpose of this study was to determine to what extent CRF improves cardiovascular disease(CVD)risk classification when added to traditional risk factors[21].A total of 66 371 Cooper Clinic men and women underwent a comprehensive baseline examination and were placed into categories of CRF as described previously.The sample was followed for an average of 16 years,during which time 1 621 deaths occurred as a result of CVD.As expected,there was a decreased risk of CVD mortality across higher CRF categories in both men and women.Next,traditional risk factors such as age,resting blood pressure,blood cholesterol level,diabetes,and smoking were used to predict the risk of CVD mortality in the sample.When CRF was added to the prediction equation,the accuracy of the equation was significantly improved.In other words,knowing a patients level of CRF gives the physician a better measure of their cardiovascular risk status than including only the previously mentioned traditional risk factors.This paper,along with many other CCLS papers,was instrumental in convincing the American Heart Association to recommend including measurement of cardiorespiratory fitness as a vital sign[22].

21 CRF與Ⅱ型糖尿病的發(fā)病率

目前美國(guó)成年人中肥胖和Ⅱ型糖尿病的流行程度處于歷史最高水平。肥胖和缺乏身體活動(dòng)是Ⅱ型糖尿病的兩個(gè)主要原因。因?yàn)镃RF的客觀(guān)測(cè)量比自我報(bào)告的身體活動(dòng)更能預(yù)測(cè)健康水平[22]，試圖確定CRF和BMI在庫(kù)珀診所女性中Ⅱ型糖尿病發(fā)病率的獨(dú)立和聯(lián)合相關(guān)性[23]。該樣本由6 249名看起來(lái)健康的女性組成，平均年齡為44歲，樣本分為低、中、高3種CRF類(lèi)別，同時(shí)還被分為正常體重、超重和肥胖的BMI類(lèi)別。在17年的隨訪(fǎng)期間，共發(fā)生了143例Ⅱ型糖尿病病例。與低CRF女性相比，那些中高CFR女性患Ⅱ型糖尿病的風(fēng)險(xiǎn)分別降低了14%和39%。超重或肥胖的人患有糖尿病的風(fēng)險(xiǎn)分別為正常體重的個(gè)體的2.6倍和4.6倍。在正常體重的女性中，低水平CRF與Ⅱ型糖尿病發(fā)病風(fēng)險(xiǎn)增加無(wú)顯著相關(guān)。然而，在超重和肥胖女性中，低水平CRF的Ⅱ型糖尿病風(fēng)險(xiǎn)增加3.6倍。最后，在超重和肥胖組中，與超重和肥胖但CRF屬于中高水平的女性相比，低CRF的女性患Ⅱ型糖尿病的風(fēng)險(xiǎn)顯著增加。這些結(jié)果強(qiáng)調(diào)了定期進(jìn)行體育鍛煉和維持正常體重在預(yù)防Ⅱ型糖尿病方面的重要性。

21 CRF and Incidence of Type 2 Diabetes

The current prevalence of obesity and type 2 diabetes among U.S.adults is at an all-time high.Both obesity and physical inactivity are two major contributors to type 2 diabetes.Because an objective measurement of CRF is a stronger predictor of health outcomes than self-reported physical activity[22],we sought to determine the independent and joint associations of CRF and BMI on the incidence of type 2 diabetes in Cooper Clinic women[23].The sample consisted of 6 249 apparently healthy women with a mean age of 44 years.Participants were grouped by CRF category as previously described,and were also grouped by BMI using standard cut points.During 17 years of follow-up,there were 143 incident cases of type 2 diabetes.When compared to low fit women,those who were moderately or highly fit had a 14%and 39%decreased risk of incident type 2 diabetes,respectively.When compared with normal weight individuals,those who were overweight or obese had 2.6 and 4.6 times the risk of incident diabetes,respectively.Among normal weight women,low CRF was not associated with an increased risk of incident type 2 diabetes.However,in overweight and obese women,low CRF was associated with a 3.6-fold increase in risk of type 2 diabetes.Finally,within the overweight and obese groups,unfit women had a significantly increased risk of type 2 diabetes when compared to overweight and obese fit women.These results underscore the importance of regular physical activity and maintaining a normal body weight for prevention of type 2 diabetes.

22 結(jié)語(yǔ)

庫(kù)珀研究所和庫(kù)珀診所已經(jīng)成立了50周年，在此期間收集的大量信息意義非凡。由于庫(kù)珀博士在庫(kù)珀研究所和庫(kù)珀診所成立時(shí)的遠(yuǎn)見(jiàn)卓識(shí)，CCLS數(shù)據(jù)庫(kù)目前收集了大約113 000名客戶(hù)的詳細(xì)健康信息，這些客戶(hù)經(jīng)歷了近250 000次最大跑臺(tái)運(yùn)動(dòng)測(cè)試。由于跑臺(tái)測(cè)試為CRF提供了的客觀(guān)測(cè)量，已經(jīng)能夠檢查CRF與各種發(fā)病率和死亡率結(jié)果的相關(guān)性。除極少數(shù)案例外，無(wú)論研究何種健康結(jié)果，都證明了相對(duì)于低水平CRF，具有中高水平的CRF可實(shí)質(zhì)性預(yù)防多種疾病。正如庫(kù)珀博士常說(shuō)的那樣：“如果定期運(yùn)動(dòng)的益處可以做成藥丸，它將是有史以來(lái)被最廣泛使用和最有益的藥方。”

22 Summary

As we approach the 50th anniversary of The Cooper Institute and Cooper Clinic,the sheer volume of information that has been collected over that time is quite extraordinary.Because of Dr.Cooper’s foresight at the time that The Cooper Institute and Cooper Clinic were founded,the CCLS database currently houses detailed health information on approximately 113 000 patients who have undergone nearly 250 000 maximal treadmill exercise tests.Because the treadmill test provides an objective measure of CRF,we have been able to examine the association of CRF with a wide variety of morbidity and mortality outcomes.With rare exception,regardless of the outcome being studied,we have shown that having a moderate to high level of CRF provides substantial protection from many adverse health outcomes,relative to having a low level of CRF.As Dr.Cooper is fond of saying“If the benefits of regular exercise could be put into a pill,it would be the most widely used and most beneficial medication ever developed.”