庫珀中心縱向研究：有氧運動的靈魂

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

0 前言

規律性的體力活動能夠有效降低多種類型疾病發病率和死亡率。雖然，從目前來看，大家已經對這二者的關系達成了共識，但幾十年前幾乎沒有任何證據支持這一觀點。20世紀50年代末到60年代肯尼斯·庫珀（Kenneth H.Cooper）博士在美國空軍任職期間，確信經常鍛煉是預防疾病和保持身體健康的關鍵之一。他于1970年12月建立庫珀研究所，因為他知道只有精心設計的研究才能證明他認定的事實。因此，當庫珀診所在此后不久剛剛開業時，庫珀博士開始對客戶進行細致記錄，并有遠見地意識到需要追蹤這些客戶的發病率和死亡率。于是，有氧運動中心縱向研究（Aerobics Center Longitudinal Study，ACLS）誕生了，ACLS的主要目的是檢查預防醫學中心的心肺健康（Cardiorespiratory fitness，CRF）與健康結果之間的關系。值得注意的是，之前與運動相關的研究主要集中在身體活動的行為方面，而那時身體活動是通過問卷調查估算的。與身體活動不同，心肺健康可以通過最大跑臺運動測試 （Maximal Treadmill Exercise Testing）客觀測量。在ACLS啟動時，并沒有關于心肺健康水平與重要健康結果之間關聯的文獻數據。因此，最大跑臺運動測試很快成為ACLS的一個組成部分。

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與庫珀中心縱向研究之間的差異

ACLS是評估健康生活方式選擇與各種結果（包括疾病、殘疾和死亡率）之間關系的高效資源。庫珀中心縱向研究（CooperCenterLongitudinalStudy，CCLS）代表了ACLS的成熟和擴展版本，增加了變量、生物材料和更多的結果 （截至2014年的新增的死亡率，醫療保險數據和德克薩斯癌癥登記處數據）。CCLS的整體樣本量明顯大于ACLS，因此具有更多的發病率和死亡率數據。

兩個研究的數據之間也存在其他重要差異。CCLS數據集額外包含血液指標 （包括維生素D水平、Omega-3指數、肝炎篩查），老年人篩查[包括蒙特利爾認知評估（Montreal Cognitive Assessment，Mo-CA）和起立行走測試（Get Up and Go）評估]，高敏感性心肌肌鈣蛋白T水平，以及遺傳物質。有關CCLS中新增內容的更多詳細信息參見下文。

目前，有112 789名客戶累計訪問庫珀診所達314 991次，已經進行了近250 000次最大跑臺運動測試；庫珀診所有著世界上最大的心肺健康數據庫。CCLS具有許多獨特且非常寶貴的特性：客戶通常是健康的、數據庫相當大、進行長期隨訪。此外，仍需強調的是，最大跑臺運動測試提供了CRF的客觀測量結果。正如頂尖的健康專家們經常說的那樣：“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?！?/p>

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

庫珀診所的客戶主要來源于自主入診人群，盡管大約三分之一的客戶是由其雇主推介而來。該診所每年診斷客戶6 000～8 000名，其中75%的客戶是回訪人群。臨床訪問者之間的問診間隔各有不同。一般而言，老年客戶往往比年輕客戶更頻繁地回訪。超過90%的臨床客戶同意參加CCLS。值得注意的是，庫珀診所的客戶并不代表美國人口的隨機樣本。庫珀診所客戶主要是非西班牙裔白人，受過高等教育，并且具有中上等級的社會經濟地位。在CCLS數據庫中，男性的數量多于女性，比例約為3:1。因此，就整體美國人口的普適化而言，數據和研究結果存在一些局限性。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，與選擇參加國家健康和營養檢驗調查（National Health and Nutrition Examination Survey，NHANES）的男性和女性的隨機樣本相比較的結果。

圖1 CCLS男性和女性的最大MET值代表的CRF與選擇參加國家健康和營養檢驗調查中男性和女性的隨機樣本比較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 庫珀診所檢查

庫珀診所檢查的指標根據客戶的年齡、性別和健康狀況而有所不同。因為對每個客戶都收集數千個變量，本文只提及一些最重要的變量。在完成知情同意后，有關年齡、性別、婚姻狀況、種族、教育程度、當前和之前的吸煙狀況、飲酒、就業狀況、當前和之前的健康狀況和癥狀、家族病史、飲食習慣、身體活動的信息（頻率、強度、持續時間和類型）、訪問次數、訪問原因、安全習慣、心理狀態和藥物使用情況等信息均通過大范圍的醫療問卷收集。雖然自2008年以來，藥物使用情況已經常規地包含在數據庫中，但數據庫目前尚未提供診所早期的藥物使用情況。體重情況通過測量身體質量指數 （Body mass index，BMI）和體脂百分比來確定。從歷史上看，診所也采用流體靜力學評估體脂。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，C反應蛋白（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，全血細胞計數（Complete blood count，CBC），Omega-3指數和血紅蛋白A1c。尿液分析用以測量pH值、比重和酮類變量，以及確定樣品中是否存在葡萄糖或蛋白質，庫珀診所還會進行視力、聽力和肺功能測試。

庫珀診在做最大跑臺運動測試時所采用改良的Balke方案[3]，其運動持續時間比更常用的Bruce方案更長。庫珀博士更喜歡改良的Balke方案，因為它可以非常緩慢地增加負荷、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。由于改良的 Balke方案比Bruce方案花費的時間更長，因此可以更清晰地分析健康水平。改良的Balke跑臺方案如下：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開始坡度不變，速度每分鐘增加5.4 m/min。在跑臺運動測試期間收集的變量包括靜息心率和血壓，以及靜息心電圖。在運動測試期間和之后，收集關于心率、血壓和ECG反應的數據。跑臺的最終速度和等級用于計算最大MET值，后者又反過來被用于確定基于年齡和性別的心肺健康類別。

客戶也可以進行影像學檢查，把其作為臨床檢查的一部分。自1997年以來，庫珀診所已對超過40 000名客戶進行了超過77 000次計算機斷層掃描。對這部分人群進行了廣泛監測，以確定其縱向心血管健康狀況，并結合CCLS中的其他成像研究 （包括DEXA掃描、超聲心動圖和頸動脈研究）。一個生物資料庫（Biobank）從2008年9月開始運行，以建立一個DNA和血液樣本制品檔案，用以進行基于與健康生活選擇相關的基因環境相互作用的研究。這項工作可以識別出與負責常見疾病有關的基因，并了解常見疾病治療和預防情況。目前，庫珀研究所存儲的DNA和冷凍血漿中存有超過13 000件個人標本。

在庫珀診所獲取的CCLS數據不是基于系統的研究方案，而是基于前文提到的預防性健康評估和客戶特定的臨床建議，因此造成了隨訪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，客戶回訪沒有特定的時間間隔。此外還存在包括客戶在訪問時通常是健康的，但只有在他們生病時才重返診所等挑戰。CCLS數據庫由庫珀研究所維護，該組織是一個非營利性的獨立研究中心，其總體研究目標是評估生活方式行為和特征對健康的影響。庫珀研究所執行嚴格的隱私保護措施。數據收集和知情同意過程每年均需要由庫珀研究所的機構倫理審查委員會審查和批準。

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 死亡率監測

截至2014年12月31日，通過NDIPlus（國家死亡指數）提供的信息，CCLS涉及的人群中有14 546人死亡。與美國人口的整體情況相似，CCLS中最常見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 發病率監測

庫珀中心除了使用回訪期間收集的數據外，還使用回信調查進行發病率監測。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卷。并于2011年向接受電子束斷層掃描檢查的人群發送了一份調查問卷。多年來問卷的回收率為50%～75%。受訪者未完成調查的最常見原因是花費了太多時間、客戶不感興趣，或客戶已搬家且沒有更新地址。

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 醫療保險（Medicare）

1971—2009年在庫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年的醫療保險資格，并與醫療保險和醫療補助服務中心（Centers for Medicare and Medicaid Services，CMS）的數據庫相匹配。該群組的可用數據包括醫療保險和醫療補助服務中心提供的經過算法驗證的慢性病癥庫中的疾病診斷和最早病兆出現日期。還有個人國際疾病分類 -9信息 （International Classification of Diseases-9）和住院及門診索賠的編碼及費用等其他可用信息。醫療保險數據為其他CCLS發病率監測提供了獨特的補充，并有可能回答有關生活方式和預防對健康老齡化、生活質量和醫療系統資源利用模式的長期影響的問題。值得注意的是，醫療保險數據本質上是行政性的，并不代替臨床診斷的結果或詳細的醫療記錄。例如，從醫療保險數據中提取的中風或高血壓的診斷不能提供血壓測量或診斷時的任何其他檢查結果。此外，由于醫療保險數據僅在1999—2009年可用，因此通常難以獲取65歲以上參與者的完整醫療保險體驗。

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據，其中包括1995年至2007年期間德克薩斯州居民的CCLS被研究者中發生癌癥事件的信息，這些數據確定了約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

在過去47年中，CCLS數據顯示，具有中高水平的心肺功能與許多重要的健康益處相關，包括降低全因、心血管和癌癥死亡率。從發病率的角度來看，保持健康與降低冠心病、中風、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險有關。下文將對這些研究進行充分討論。

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 心肺健康與冠狀動脈危險因素

20世紀70年代早期，有一些證據表明身體活動對冠心病具有保護作用，但其機制在很大程度上是未知的。庫珀博士是研究平均年齡為45歲的3 000名男性（他們在1970—1974年間進行了檢查[4]）客觀測量的心肺功能（Cardiorespiratory fitness，CRF）與冠狀動脈危險因素之間關聯的第一人。根據年齡和最大跑臺運動測試表現，將男性CRF按五分位數（Quintile）分為5類，在CRF五分位數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。觀察到CRF與所有這些變量之間呈負相關。即使將CRF的最低五分位數與下一個最高五分位數進行比較，也可以顯示出這種關系。這是第一項報告客觀測量的心肺功能與冠狀動脈危險因素關聯性的研究，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，庫珀研究所和庫珀診所的研究人員發表了被認為具有里程碑意義的CCLS論文[5]。該論文發表在美國醫學會雜志（JAMA）上，報告了13 344名平均年齡為45歲的男性和女性在基線綜合預防性檢查后接受了超過8年的隨訪。根據他們的最大跑臺運動測試表現，以及年齡和性別，對每個客戶的CRF按五分位數進行分類，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。在隨訪期間，有283名全因死亡。在隨訪期間發現基線CRF與死亡風險之間存在顯著的負相關，換句話說，與基線時低CRF的男性和女性相比，在基線時中高水平CRF的男性和女性在隨訪期間死亡的可能性大大降低。當對Quintile1和Quintile2進行比較時，顯示出現風險差異最大，這是第一項明確證明CRF是男性和女性全因死亡率的重要且獨立預測因子的研究。

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，冠狀動脈鈣化和心血管事件

近年來，冠狀動脈鈣化（Coronary artery calcium，CAC）評分一直是研究者預測未來心血管疾病發生風險的主要研究課題。雖然CRF和CAC分別對心血管疾病發生風險預測有很大貢獻，但令人驚訝的是，人們對CRF如何影響不同類別CAC的心血管疾病風險仍知之甚少?？紤]到這一點，1998年至2007年間檢測的8 425名年齡在30～80歲之間的健康庫珀診所男性樣本中檢查這些關系[6]，對他們的綜合檢測包括測量CRF的最大跑臺運動測試、確定CAC評分的CT掃描，以及傳統心血管疾病危險因素的仔細測量。跟蹤樣本時間平均為8.4年，在此期間發生了383個致命和非致命的心血管疾病發生案列。CAC評分為0的男性心血管疾病發生風險發生率非常低 （1 000人每年發生1.3次事件），而CAC評分≥400的男性心血管疾病發生風險發生率則大大增高（1 000人每年發生18.9次事件）。根據以前的研究，這一結果是預料之中的。一項包括CRF的新的研究結果如圖2所示，圖2顯示了基線檢查后15年內4個CAC類別在不同CRF水平的心血管疾病發生風險，最大年齡至70歲。在每個CAC類別中，心血管疾病發生風險隨著CRF水平的增加而降低。在CAC評分較高的男性中，CRF風險降低更為明顯。如圖2所示，CAC評分為0的非常健康的男性疾病發生風險最低，而CAC評分≥400的非常不健康的男性疾病發生風險最高。需要強調的是，較高水平的CRF可在所有4種CAC類別中對心血管疾病發生風險提供一定程度的保護。

圖2 基線檢查后15年內4個CAC類別在不同CRF水平的心血管疾病發生風險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與慢性病的發展

年齡的增長與心臟病和糖尿病等幾種慢性疾病的發展密切相關。2012年，我們檢查了中年CRF與老年非致命性慢性病發展之間的關系[7]。研究對象由來自庫珀診所的18 670名看起來健康的男性和女性組成，平均年齡為49歲，他們接受了基線預防性檢查，并確定可以在1999—2009年期間接受醫療保險，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、糖尿病、慢性阻塞性肺病、慢性腎病、阿爾茨海默病和結腸癌或肺癌。將受試者按CRF的五分位數分類，從基線檢查開始的平均隨訪時間為26年。將最低CRF五分位數的男性與CRF最高五分位數的男性進行比較，未來CC的發生比率分別為每年每10人出現了2.82和每年每10人出現了1.56/10人。將最低CRF五分位數的女性與最高CRF五分位數的女性進行比較，未來CC的比率分別為每年2.01/10人和1.14/10人。因此，中年時較高水平的CRF與晚年患慢性病的風險降低顯著相關，見圖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

隨著美國人口平均年齡的持續增加，全因癡呆癥已成為老年人的主要健康問題。因此，庫珀診所檢查了中年CRF與全因癡呆未來發展風險之間的關聯，這一點已經過醫療保險數據驗證[8]。研究對象為包括19 458名健康男性和女性，平均年齡為49歲。將受試者按CRF的五分位數分類，在25年的隨訪期間，發生了1 659例全因癡呆病例。CRF最高分位數的受試者發生全因癡呆的可能性比最低五分位數的受試者低36%。重要的是，這是第一項顯示中年CRF與未來全因癡呆風險之間顯著相關的研究。

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中很常見。使用CCLS和醫療保險數據，我們檢查了中年CRF與CKD發生風險的關系[9]。研究對象包括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年接受醫療保險。在每年116 973人的醫療保險追蹤中共發生2 022例CKD，與較低健康水平者相比，中等水平和高水平CRF研究對象發生CKD的可能性分別低24%和34%，即使在隨訪期間患上糖尿病的客戶中，CRF每增加1 MET，CKD的風險也會降低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與中風風險

在美國，中風是造成長期殘疾的主要原因，也是導致死亡的主要原因之一。盡管低水平的CRF已成為中風的一個強大且獨立的危險因素[10]，但尚不清楚這種相關性在何種程度上可通過糖尿病、高血壓和心房顫動等中風危險因素的發展來解釋。庫珀診所檢查了中年CRF與65歲以后中風風險之間的關系，并排除上述風險因素的影響[11]，共有19 815名在基線時平均年齡為50歲的庫珀診所客戶參與了該研究。所有人看起來都很健康，且在檢驗時中風風險相對較低?；谒麄兊呐芘_運動測試表現，將每個個體劃分為低、中或高CRF類別。共有每年129 436人的醫療保險隨訪數據，在此期間發生了808例中風住院治療案例。重要的是，在分析中還仔細考慮了在臨床檢查時可能未檢測的中風時的高血壓、糖尿病或心房顫動的數據。使用低CRF組作為對照組，在醫療保險隨訪期間，中年時期中等水平CRF和高水平CRF研究對象因中風住院治療的可能性分別為24%和37%。重要的是，這些數字是在考慮了基線時出現的中風危險因素以及中風診斷時出現的中風危險因素后確定的。因此，無論在研究期間的任何時間是否存在高血壓、糖尿病或心房顫動，CRF仍然是中風住院風險的很有效的預測因子。

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與癌癥發病率和癌癥存活率

癌癥是美國第二大死亡原因。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。庫珀診所試圖通過利用CCLS和醫療保險數據來檢查中年CRF與肺癌、前列腺癌和結直腸癌之間的關系，以及中年CRF與癌癥診斷后存活率的關系[12]。1971—2009年期間，庫珀診所共檢查了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，肺癌和結直腸癌發病風險分別降低17%和9%。我們推測，較高健康程度男性的前列腺癌發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療保健篩查。在醫療保險年齡范圍內被診斷患有癌癥的男性中，觀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65歲及以上人群住院治療的最常見原因之一。通過結合CCLS數據與醫療保險數據，庫珀診所在19 485名男性和女性中檢查了中年CRF與因HF住院產生的CRF變化之間的關系[13]。在對基線檢查的傳統HF風險因素進行調整后，較高水平CRF與HF住院風險的降低有關，每增加1 MET的跑臺運動測試成績，HF住院風險降低18%。一部分客戶（n=8 683）接受了第二次檢查，距基線檢查的平均時間為4.2年。在基線檢查時健康（Quintile2-5）且持續保持健康的個體后續HF住院的風險最低。相反，在基線檢查時不健康（Quintile1）且仍持續不健康的個體HF住院的風險最高?；€時不健康但進行隨訪檢查時恢復健康的個體有中等程度的HF住院治療風險。

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

雖然已有文獻報道了身體活動與心力衰竭之間的關聯，但迄今為止沒有研究檢查過客觀測量的CRF與心力衰竭死亡率之間的關系。庫珀診所追蹤了44 674名庫珀診所男性，平均年齡為19.8歲[14]。在基線檢查時，所有男性看起來都很健康，按CRF水平分為低、中、高組，且基于標準BMI類別被分類為正常體重、超重或肥胖。在隨訪期間，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，在具有相同數量HF風險因素的男性中，中高CRF男性死于HF的可能性大大低于低CRF男性。例如，對于有1個HF危險因素的男性來說，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 健康行為和長期醫療保健費用

17.1 老年CRF與醫療保健費用

雖然普遍認為中年心血管危險因素與以后的醫療保健成本相關，但與這些風險因素無關的CRF對醫療保健成本影響的數據仍舊匱乏。研究了19 571名健康男性和女性，平均年齡為49歲，他們在庫珀診所接受檢查，隨后在1999—2009年期間接受了醫療保險[15]，按CRF水平分為低、中、高組。醫療保險的平均隨訪時間為6.5年，共計每年126 388人的數據。當比較中年高水平CRF和低水平CRF的參與者時，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）的平均年度醫療保健費用顯著降低。根據心血管危險因素進行調整后，CRF每增加1 MET，男性和女性的平均年度醫療保健費用分別降低6.8%和6.7%。

17.2 簡單生活7要素（Life's Simple 7）與長期醫療保健費用

美國心臟協會開發了“Life's Simple 7”，囊括了與心血管健康密切相關的行為和因素[16]。包括飲食、身體活動、吸煙、體重指數、血液膽固醇、血糖和靜息血壓。每個要素分為較差、中等或理想3個水平。把7要素達到理想水平的狀態定義為理想的心血管健康。為了評估這7個要素的經濟影響，對1999—2009年期間入選醫療保險的4 906名庫珀診所平均年齡為56的中年男性和女性樣本進行了評估[17]。根據他們的基線檢查結果，將他們分為3個等級：（1）不利，具有0～2項理想心血管健康特征；（2）中等，具有3～4 項理想心血管健康特征；（3）有利，具有 5～7 項理想心血管健康特征。不到1%的參與者具有所有7個理想特征，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療保險費用為5 058美元，而有利組為3 883美元。年均心血管疾病費用中也有相同趨勢 （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量的理想心血管健康特征與晚年的醫療保健成本成顯著負相關。

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與代謝綜合征的發生率

代謝綜合征（Metabolic syndrome，MetSyn）是一種常見病癥，具有以下至少3項表現：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。患有MetSyn的個體全因和心血管死亡的風險增加。CCLS以前的研究表明，中高CRF女性與低CRF女性MetSyn的發生率更低[18]。該研究的目的是確定健康人的基線CRF是否是MetSyn的預測因子。1979—2003年期間，共有9 007名男性和1 491名女性在基線檢查時沒有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水平女性發展MetSyn的可能性分別為20%和63%[19]。這項研究首次表明，低水平CRF是男性和女性MetSyn的有效因子，因此，在許多情況下，可以通過簡單地實現中等至高水平的CRF來預防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

雖然體重狀態和CRF都是重要的健康指標，但這是第一項旨在比較CRF與體重狀態在死亡風險方面重要性的CCLS研究[20]。將25 389名庫珀診所男性樣本分為低、中、高3種CRF類別，同時還被分為正常體重、超重和肥胖的BMI類別，以研究上述兩因素與死亡風險之間的關系。在平均8.5年的隨訪期間共有673人死亡。在每個BMI類別中，在CRF水平較高的情況下，全因死亡率的風險顯著降低。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。這是第一項顯示CRF與死亡率相關性高于BMI的研究。因此，在所有BMI類別中都可以看到具有中高水平CRF的益處。這項重要的研究為許多未來探討 “健康與肥胖”問題的CCLS研究奠定了基礎。

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與心血管風險分類

心血管疾?。–ardiovascular disease，CVD）是導致居住在生活水平較高的國家的成年人死亡的主要原因之一。CVD的傳統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、不活動和肥胖。在過去的30年中，低水平的CRF已經成為一個非常強大和獨立的CVD風險因素。盡管已經開發出許多預測未來心血管疾病風險的公式，但這些公式都沒有把CRF水平包括在共識的風險因素中。事實上，CRF通常是在體檢期間非常規測量的唯一主要風險因素。本研究的目的是確定當加入傳統危險因素時，CRF在多大程度上能降低CVD的風險[21]。研究共有66 371名庫珀診所男性和女性接受了全面的基線檢查，按CRF水平進行分類。樣本平均跟蹤時間為16年，在此期間CVD導致1 621例死亡。正如預期的那樣，男性和女性的CRF水平與CVD死亡風險降低有關。接下來，使用傳統的風險因素，如年齡、靜息血壓、血膽固醇水平、糖尿病和吸煙，來預測樣本中CVD死亡的風險。當CRF被添加到預測公式中時，方程的準確性得到顯著改善。換句話說，了解客戶的CRF水平可以讓醫生更好地評價他們的CVD發生風險。該研究與許多其他CCLS論文一起，有助于建議美國心臟協會將心肺健康測量作為一個評價CVD發生風險的重要標志[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型糖尿病的發病率

目前美國成年人中肥胖和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是Ⅱ型糖尿病的兩個主要原因。因為CRF的客觀測量比自我報告的身體活動更能預測健康水平[22]，試圖確定CRF和BMI在庫珀診所女性中Ⅱ型糖尿病發病率的獨立和聯合相關性[23]。該樣本由6 249名看起來健康的女性組成，平均年齡為44歲，樣本分為低、中、高3種CRF類別，同時還被分為正常體重、超重和肥胖的BMI類別。在17年的隨訪期間，共發生了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型糖尿病的風險分別降低了14%和39%。超重或肥胖的人患有糖尿病的風險分別為正常體重的個體的2.6倍和4.6倍。在正常體重的女性中，低水平CRF與Ⅱ型糖尿病發病風險增加無顯著相關。然而，在超重和肥胖女性中，低水平CRF的Ⅱ型糖尿病風險增加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型糖尿病的風險顯著增加。這些結果強調了定期進行體育鍛煉和維持正常體重在預防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 結語

庫珀研究所和庫珀診所已經成立了50周年，在此期間收集的大量信息意義非凡。由于庫珀博士在庫珀研究所和庫珀診所成立時的遠見卓識，CCLS數據庫目前收集了大約113 000名客戶的詳細健康信息，這些客戶經歷了近250 000次最大跑臺運動測試。由于跑臺測試為CRF提供了的客觀測量，已經能夠檢查CRF與各種發病率和死亡率結果的相關性。除極少數案例外，無論研究何種健康結果，都證明了相對于低水平CRF，具有中高水平的CRF可實質性預防多種疾病。正如庫珀博士常說的那樣：“如果定期運動的益處可以做成藥丸，它將是有史以來被最廣泛使用和最有益的藥方?！?/p>

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.”