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1.  Association between muscular strength and mortality in men: prospective cohort study 
BMJ : British Medical Journal  2008;337(7661):92-95.
Objective To examine prospectively the association between muscular strength and mortality from all causes, cardiovascular disease, and cancer in men.
Design Prospective cohort study.
Setting Aerobics centre longitudinal study.
Participants 8762 men aged 20-80.
Main outcome measures All cause mortality up to 31 December 2003; muscular strength, quantified by combining one repetition maximal measures for leg and bench presses and further categorised as age specific thirds of the combined strength variable; and cardiorespiratory fitness assessed by a maximal exercise test on a treadmill.
Results During an average follow-up of 18.9 years, 503 deaths occurred (145 cardiovascular disease, 199 cancer). Age adjusted death rates per 10 000 person years across incremental thirds of muscular strength were 38.9, 25.9, and 26.6 for all causes; 12.1, 7.6, and 6.6 for cardiovascular disease; and 6.1, 4.9, and 4.2 for cancer (all P<0.01 for linear trend). After adjusting for age, physical activity, smoking, alcohol intake, body mass index, baseline medical conditions, and family history of cardiovascular disease, hazard ratios across incremental thirds of muscular strength for all cause mortality were 1.0 (referent), 0.72 (95% confidence interval 0.58 to 0.90), and 0.77 (0.62 to 0.96); for death from cardiovascular disease were 1.0 (referent), 0.74 (0.50 to 1.10), and 0.71 (0.47 to 1.07); and for death from cancer were 1.0 (referent), 0.72 (0.51 to 1.00), and 0.68 (0.48 to 0.97). The pattern of the association between muscular strength and death from all causes and cancer persisted after further adjustment for cardiorespiratory fitness; however, the association between muscular strength and death from cardiovascular disease was attenuated after further adjustment for cardiorespiratory fitness.
Conclusion Muscular strength is inversely and independently associated with death from all causes and cancer in men, even after adjusting for cardiorespiratory fitness and other potential confounders.
PMCID: PMC2453303  PMID: 18595904
2.  Muscular strength and adiposity as predictors of adulthood cancer mortality in men 
We examined the associations between muscular strength, markers of overall and central adiposity and cancer mortality in men.
Prospective cohort study including 8,677 men aged 20-82 years followed from 1980 to 2003. Participants were enrolled in The Aerobics Centre Longitudinal Study, the Cooper Clinic in Dallas, Texas, U.S. Muscular strength was quantified by combining 1-repetition maximal measures for leg and bench presses. Adiposity was assessed by body mass index (BMI), percent body fat, and waist circumference.
Cancer death rates per 10,000 person-years adjusted for age and examination year were: 17.5, 11.0, and 10.3 across incremental thirds of muscular strength (P=0.001); 10.9, 13.4, and 20.1 across BMI groups of 18.5-24.9, 25.0-29.9, and ≥30kg/m2, respectively (P=0.008); 11.6 and 17.5 for normal (<25%) and high percent body fat (≥25%), respectively (P=0.006); and 12.2 and 16.7 for normal (≤102 cm) and high waist circumference (>102 cm), respectively (P=0.06). After adjusting for additional potential confounders, hazard ratios (95% confidence intervals) were 1.00 (referent), 0.65 (0.47-0.90), and 0.61 (0.44-0.85) across incremental thirds of muscular strength, respectively (P=0.003 for linear trend). Further adjustment for BMI, percent body fat, waist circumference, or cardiorespiratory fitness had little effect on the association. The associations of BMI, percent body fat, or waist circumference with cancer mortality did not persist after further adjusting for muscular strength (all P≥0.1).
Higher levels of muscular strength are associated with lower cancer mortality risk in men, independent of clinically established measures of overall and central adiposity, and other potential confounders.
PMCID: PMC3762582  PMID: 19366909
Muscular strength; obesity; cancer; cardiorespiratory fitness; resistance exercise
3.  A Prospective Study of Muscular Strength and All-cause Mortality in Men with Hypertension 
To assess the impact of muscular strength on mortality in men with hypertension.
Muscular strength is inversely associated with mortality in healthy men, but this association has not been examined in men with hypertension.
We followed 1506 hypertensive men aged ≥ 40 years enrolled in the Aerobics Center Longitudinal Study from 1980 to 2003. Participants received an extensive medical examination at baseline. Muscular strength was quantified by combining one repetition maximum (1-RM) measures for leg and bench press, and cardiorespiratory fitness (CRF) assessed by maximum exercise test on a treadmill.
During an average follow-up of 18.3 years, 183 deaths occurred. Age adjusted death rates per 10 000 man-years across incremental thirds of muscular strength were 81.8, 65.5 and 52.0 (P<0.05 for linear trend). Multivariable Cox regression hazard ratios were 1.0 (reference), 0.81 (95% confidence interval, 0.57 to 1.14), and 0.59 (0.40 to 0.86) across incremental thirds of muscular strength. After further adjustment for CRF, those participants in the upper third of muscular strength still had a lower risk of death (0.66; 0.45 to 0.98). In the muscular strength and CRF combined analysis, men simultaneously in the upper third of muscular strength and high fitness group had the lowest mortality risk among all combination groups (0.49; 0.30 to 0.82), with men in the lower third of muscular strength and low fitness group as reference.
High levels of muscular strength appear to protect hypertensive men against all-cause mortality, and this is in addition to the benefit provided by CRF.
PMCID: PMC3098120  PMID: 21527158
Hypertension; muscular strength; cardiorespiratory fitness; mortality
4.  Muscular Strength and Incident Hypertension in Normotensive and Prehypertensive Men 
The protective effects of cardiorespiratory fitness (CRF) on hypertension (HTN) are well known; however, the association between muscular strength and incidence of HTN has yet to be examined.
This study evaluated the strength-HTN association with and without accounting for CRF.
Participants were 4147 men (20–82 years) in the Aerobics Center Longitudinal Study for whom an age-specific composite muscular strength score was computed from measures of a 1-repetition maximal leg and a 1-repetition maximal bench press. CRF was quantified by maximal treadmill exercise test time in minutes. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals of incident HTN events according to exposure categories.
During a mean follow-up of 19 years, there were 503 incident HTN cases. Multivariable-adjusted (excluding CRF) HRs of hypertension in normotensive men comparing middle and high strength thirds to the lowest third were not significant at 1.17 and 0.84, respectively. Multivariable-adjusted (excluding CRF) HRs of hypertension in baseline prehypertensive men comparing middle and high strength thirds to the lowest third were significant at 0.73 and 0.72 (p=.01 each), respectively. The association between muscular strength and incidence of HTN in baseline prehypertensive men was no longer significant after control for CRF (p=.26).
The study indicated that middle and high levels of muscular strength were associated with a reduced risk of HTN in prehypertensive men only. However, this relationship was no longer significant after controlling for CRF.
PMCID: PMC2809142  PMID: 19927030
physical fitness; blood pressure; cohort study; epidemiology
5.  Muscular strength in male adolescents and premature death: cohort study of one million participants 
Objectives To explore the extent to which muscular strength in adolescence is associated with all cause and cause specific premature mortality (<55 years).
Design Prospective cohort study.
Setting Sweden.
Participants 1 142 599 Swedish male adolescents aged 16-19 years were followed over a period of 24 years.
Main outcome measures Baseline examinations included knee extension, handgrip, and elbow flexion strength tests, as well as measures of diastolic and systolic blood pressure and body mass index. Cox regression was used to estimate hazard ratios for mortality according to muscular strength categories (tenths).
Results During a median follow-up period of 24 years, 26 145 participants died. Suicide was a more frequent cause of death in young adulthood (22.3%) than was cardiovascular diseases (7.8%) or cancer (14.9%). High muscular strength in adolescence, as assessed by knee extension and handgrip tests, was associated with a 20-35% lower risk of premature mortality due to any cause or cardiovascular disease, independently of body mass index or blood pressure; no association was observed with mortality due to cancer. Stronger adolescents had a 20-30% lower risk of death from suicide and were 15-65% less likely to have any psychiatric diagnosis (such as schizophrenia and mood disorders). Adolescents in the lowest tenth of muscular strength showed by far the highest risk of mortality for different causes. All cause mortality rates (per 100 000 person years) ranged between 122.3 and 86.9 for the weakest and strongest adolescents; corresponding figures were 9.5 and 5.6 for mortality due to cardiovascular diseases and 24.6 and 16.9 for mortality due to suicide.
Conclusions Low muscular strength in adolescents is an emerging risk factor for major causes of death in young adulthood, such as suicide and cardiovascular diseases. The effect size observed for all cause mortality was equivalent to that for well established risk factors such as elevated body mass index or blood pressure.
PMCID: PMC3502746  PMID: 23169869
6.  Effects of Muscular Strength on Cardiovascular Risk Factors and Prognosis 
Physical fitness is one of the strongest predictors of individual future health status. Together with cardiorespiratory fitness (CRF), muscular strength (MusS) has been increasingly recognized in the pathogenesis and prevention of chronic disease. We review the most recent literature on the effect of MusS in the development of cardiovascular disease (CVD), with special interest in elucidating its specific benefits beyond those from CRF and body composition. MusS has shown an independent protective effect on all-cause and cancer mortality in healthy middle-aged men, as well as in men with hypertension (HTN) and patients with heart failure. It has also been inversely associated with age-related weight and adiposity gains, risk of HTN, and prevalence and incidence of the metabolic syndrome. In children and adolescents, higher levels of muscular fitness have been inversely associated with insulin resistance, clustered cardiometabolic risk and inflammatory proteins. Generally, the influence of muscular fitness was weakened but remained protective after considering CRF. Also interestingly, higher levels of muscular fitness seems to some extent counteract the adverse cardiovascular profile of overweight and obese individuals. As many of the investigations have been conducted with non-Hispanic white men, it is important to examine how race/ethnicity and gender may affect these relationships. To conclude, most important effects of resistance training (RT) are also summarized, to better understand how higher levels of muscular fitness may result in a better cardiovascular prognosis and survival.
PMCID: PMC3496010  PMID: 22885613
muscular strength; cardiorespiratory fitness; cardiovascular disease; resistance training
7.  Differences in Physical Fitness and Cardiovascular Function Depend on BMI in Korean Men 
We investigated the associations between cardiovascular function and both body mass index and physical fitness in Korean men. The subjects were 2,013 men, aged 20 to 83 years, who visited a health promotion center for a comprehensive medical and fitness test during 2006-2009. The WHO's Asia-Pacific Standard Report definition of BMI was used in this study. Fitness assessment of cardiorespiratory endurance, muscular strength, muscular endurance, flexibility, power, agility, and balance were evaluated by VO2max (ml/kg/min), grip strength (kg), sit-ups (reps/min), sit and reach (cm), vertical jump (cm), side steps (reps/30s), and standing on one leg with eyes closed (sec), respectively. For cardiovascular function, we evaluated systolic blood pressure (SBP), diastolic blood pressure (DBP), resting heart rate (RHR), double product (DP), and vital capacity. There were significant decreases in cardiorespiratory endurance (p < 0.001), power (p < 0.001), and balance (p < 0.001), and increases in muscular strength (p < 0.001). Further, cardiovascular function, including SBP (p < 0.001), DBP (p < 0.001), double product (p < 0.001), and vital capacity (p=0.006) appeared to be lower for the obesity group. We conclude that an obese person exhibits lower fitness level and weaker cardiovascular function than a normal person.
Key pointsThe obese group had a lower fitness level, including cardiorespiratory endurance, power, and balance.Obese group demonstrated an increase in muscular strength.Obese group had higher blood pressure and weaker cardiovascular function, including DP and vital capacity, than the normal group.
PMCID: PMC3761729  PMID: 24149691
Body mass index; obesity; physical fitness; cardiovascular function
8.  Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in Men: The Aerobics Center Longitudinal Study 
Circulation  2011;124(23):2483-2490.
The combined associations of changes in cardiorespiratory fitness and body mass index (BMI) with mortality remain controversial and uncertain.
Methods and Results
We examined the independent and combined associations of changes in fitness and BMI with all-cause and cardiovascular disease (CVD) mortality in 14 345 men (mean age 44 years) with at least two medical examinations. Fitness, in metabolic equivalents (METs), was estimated from a maximal treadmill test. BMI was calculated using measured weight and height. Changes in fitness and BMI between the baseline and last examinations over 6.3 years were classified into loss, stable, or gain groups. During 11.4 years of follow-up after the last examination, 914 all-cause and 300 CVD deaths occurred. The hazard ratios (95% confidence intervals) of all-cause and CVD mortality were 0.70 (0.59 to 0.83) and 0.73 (0.54 to 0.98) for stable fitness, and 0.61 (0.51 to 0.73) and 0.58 (0.42 to 0.80) for fitness gain, respectively, compared with fitness loss in multivariable analyses including BMI change. Every 1-MET improvement was associated with 15% and 19% lower risk of all-cause and CVD mortality, respectively. BMI change was not associated with all-cause or CVD mortality after adjusting for possible confounders and fitness change. In the combined analyses, men who lost fitness had higher all-cause and CVD mortality risks regardless of BMI change.
Maintaining or improving fitness is associated with a lower risk of all-cause and CVD mortality in men. Preventing age-associated fitness loss is important for longevity regardless of BMI change.
PMCID: PMC3238382  PMID: 22144631
exercise capacity; obesity; mortality; cardiovascular disease; epidemiology
9.  Self-rated health status and cardiorespiratory fitness as predictors of mortality in men 
British journal of sports medicine  2011;45(14):1095-1100.
Self-rated health (SRH) and cardiorespiratory fitness (fitness) are independent risk factors for all-cause mortality. The purpose of this report is to examine the single and joint effects of these exposures on mortality risk. The study included 18,488 men who completed a health survey, clinical examination, and a maximal exercise treadmill test during 1987–2003. Cox regression analysis was used to quantify the associations of SRH and fitness with all-cause mortality. There were 262 deaths during 17 years of follow-up. There was a significant inverse trend (Ptrend < 0.05) for mortality across SRH categories after adjustment for age, examination year, body mass index, physical activity, smoking, alcohol consumption, abnormal ECG, hypertension, and hypercholesterolemia, cardiovascular disease, diabetes, and cancer. Adjustment for fitness attenuated the association (P value =0.09). We also observed an inverse association between fitness and mortality after controlling for the same covariates and SRH (Ptrend = 0.006). The combined analysis of SRH and fitness showed that fit men with good or excellent SRH had a 58% lower risk of mortality than their counterparts. SRH and fitness were both associated with all-cause mortality in men. Fit men with good or excellent SRH live longer than unfit men with poor or fair SRH.
PMCID: PMC3192266  PMID: 21659563
health status; men; mortality; physical fitness
To establish associations between leg strength and mortality in men and women with lower extremity peripheral arterial disease (PAD).
Observational, prospective study.
Chicago area medical centers.
Participants were 410 men and women with PAD age 55 and older followed for a mean of 60.0 months.
Isometric knee extension, knee flexion, hip extension, and hip flexion were measured at baseline. Primary outcomes were all-cause and cardiovascular disease mortality. Cox proportional hazards models were used to assess relations between leg strength and all-cause and cardiovascular disease mortality among men and women, adjusting for age, race, comorbidities, smoking, body mass index, and the ankle brachial index.
Among the 246 male participants, poorer baseline strength for knee flexion (P trend = .029), knee extension (P trend =.010), and hip extension (P trend = .013) were each associated independently with higher all-cause mortality. Poorer strength for knee flexion (P trend = .042) and hip extension (P trend = .029) were associated with higher cardiovascular mortality. Compared to those in the fourth (best) baseline knee flexion quartile, Hazard Ratios for all-cause and cardiovascular disease mortality among men in the 1st (poorest) knee flexion quartile were 2.23 (95% Confidence Interval (CI) = 1.02–4.87, P=.045) and 4.20 (95% CI = 1.12–15.79, P=.043), respectively. No significant associations of leg strength and all-cause mortality were identified among women.
Poorer leg strength is associated with increased mortality in men, but not women, with PAD. Future study is needed to determine whether interventions that increase leg strength improve survival in men with PAD.
PMCID: PMC3222683  PMID: 20598471
11.  Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men 
Dietary supplements containing L-arginine are marketed to improve exercise performance, but the efficacy of such supplements is not clear. Therefore, this study examined the efficacy of acute ingestion of L-arginine alpha-ketoglutarate (AAKG) muscular strength and endurance in resistance trained and untrained men.
Eight resistance trained and eight untrained healthy males ingested either 3000mg of AAKG or a placebo 45 minutes prior to a resistance exercise protocol in a randomized, double-blind crossover design. One-repetition maximum (1RM) on the standard barbell bench press and leg press were obtained. Upon determination of 1RM, subjects completed repetitions to failure at 60% 1RM on both the standard barbell bench press and leg press. Heart rate was measured pre and post exercise. One week later, subjects ingested the other supplement and performed the identical resistance exercise protocol.
Our data showed statistical significant differences (p<0.05) between resistance trained and untrained males for both 1RM and total load volume (TLV; multiply 60% of 1RM times the number of repetitions to failure) for the upper body. However, 1RM and TLV were not statistically different (p>0.05) between supplementation conditions for either resistance trained or untrained men in the bench press or leg press exercises. Heart rate was similar at the end of the upper and lower body bouts of resistance exercise with AAKG vs. placebo.
The results from our study indicate that acute AAKG supplementation provides no ergogenic benefit on 1RM or TLV as measured by the standard barbell bench press and leg press, regardless of the subjects training status.
PMCID: PMC3428651  PMID: 22510253
Resistance exercise; Ergogenic aids; Nitric oxide
12.  Occupational and leisure time physical activity: risk of all-cause mortality and myocardial infarction in the Copenhagen City Heart Study. A prospective cohort study 
BMJ Open  2012;2(1):e000556.
Men with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality. The association between occupational physical activity with cardiovascular disease and all-cause mortality may also depend on leisure time physical activity.
A prospective cohort study.
The Copenhagen City Heart Study.
7819 men and women aged 25–66 years without a history of cardiovascular disease who attended an initial examination in the Copenhagen City Heart Study in 1976–1978.
Outcome measures
Myocardial infarction and all-cause mortality. Occupational physical activity was defined by combining information from baseline (1976–1978) with reassessment in 1981–1983. Conventional risk factors were controlled for in Cox analyses.
During the follow-up from 1976 to 1978 until 2010, 2888 subjects died of all-cause mortality and 787 had a first event of myocardial infarction. Overall, occupational physical activity predicted all-cause mortality and myocardial infarction in men but not in women (test for interaction p=0.02). High occupational physical activity was associated with an increased risk of all-cause mortality among men with low (HR 1.56; 95% CI 1.11 to 2.18) and moderate (HR 1.31; 95% CI 1.05 to 1.63) leisure time physical activity but not among men with high leisure time physical activity (HR 1.00; 95% CI 0.78 to 1.26) (test for interaction p=0.04). Similar but weaker tendencies were found for myocardial infarction. Among women, occupational physical activity was not associated with subsequent all-cause mortality or myocardial infarction.
The findings suggest that high occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.
Article summary
Article focus
Men with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality.
It is unknown if the association between occupational physical activity with cardiovascular disease and all-cause mortality also depends on leisure time physical activity.
Key messages
This study shows that men with high occupational physical activity have an increased risk of all-cause mortality.
Leisure time physical activity was found to modify the positive association between occupational physical activity and risk of all-cause mortality. High occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.
Strengths and limitations of this study
Study strengths include the long follow-up time, repeated assessment of the occupational physical activity, objective measures of several covariates from clinical examinations, information on outcomes obtained from valid registers, and participation of both sexes. Some limitations are the lack of control for psychosocial work factors and the self-reported exposures.
PMCID: PMC3282285  PMID: 22331387
13.  Cardiorespiratory risk factors as predictors of 40-year mortality in women and men 
Heart  2009;95(15):1250-1257.
Most historical studies of cardiorespiratory risk factors as predictors of mortality have been based on men. This study examines whether they predict mortality over long periods in women and men.
Prospective cohort study.
Participants were employees of the General Post Office.
Risk factor data were collected via clinical examination and questionnaire, 1966–67. Associations between cardiorespiratory risk factors and 40-year mortality were determined for 644 women and 1272 men aged 35–70 at examination.
Main outcome measures
All-cause, cardiovascular (CVD), cancer, and respiratory mortality.
Associations between systolic blood pressure and all-cause and stroke mortality were equally strong for women and men, hazard ratio (95% confidence interval): 1.25 (1.1–1.4) and 1.18 (1.1–1.3); and 2.17 (1.7–2.8) and 1.69 (1.4–2.1) respectively. Cholesterol was higher in women and was associated with all-cause 1.22 (1.1–1.4) and CVD 1.39 (1.2–1.7) mortality, while associations between 2-hour glucose and all-cause 1.15 (1.1–1.2), coronary heart disease (CHD) 1.25 (1.1–1.4) and respiratory mortality 1.21 (1.0–1.5) were observed in men. Obesity was associated with stroke in women 2.42 (1.12–5.24) and CHD in men 1.59 (1.02–2.49), while ECG ischaemia was associated with CVD in both sexes. The strongest, most consistent predictor of mortality was smoking in women and poor lung function in men. However, evidence of sex differences in associations between the cardiorespiratory risk factors measured and mortality was sparse.
Data from a 40-year follow-up period show remarkably persistent associations between risk factors and cardiorespiratory and all-cause mortality in women and men.
PMCID: PMC2746941  PMID: 19389720
Adult; Aged; Blood Pressure; physiology; Body Mass Index; Cause of Death; Cohort Studies; Female; Heart Diseases; mortality; physiopathology; Humans; Male; Middle Aged; Respiratory Function Tests; Respiratory Tract Diseases; mortality; physiopathology; Risk Factors; Smoking; mortality; physiopathology; cardiorespiratory mortality; risk factors; 40-year mortality; 1960s
14.  A prospective study of social networks in relation to total mortality and cardiovascular disease in men in the USA. 
STUDY OBJECTIVE: Previous studies have established a relationship between low levels of social networks and total mortality, but few have examined cause specific mortality or disease incidence. This study aimed to examine prospectively the relationships between social networks and total and cause specific mortality, as well as cardiovascular disease incidence. DESIGN: This was a four year follow up study in an ongoing cohort of men, for whom information on social networks was collected at baseline. The main outcome measures were total mortality, further categorised into deaths from cardiovascular disease (stroke and coronary heart disease), total cancer, accidents/suicides, and all other causes; as well as stroke and coronary heart disease incidence. PARTICIPANTS: Altogether 32,624 US male health professionals aged 42 to 77 years in 1988, who were free of coronary heart disease, stroke, and cancer at baseline. RESULTS: A total of 511 deaths occurred during 122,911 person years of follow up. Compared with men with the highest level of social networks, socially isolated men (not married, fewer than six friends or relatives, no membership in church or community groups) were at increased risk for cardiovascular disease mortality (age adjusted relative risk, 1.90; 95% CI 1.07, 3.37) and deaths from accidents and suicides (age adjusted relative risk 2.22; 95% CI 0.76, 6.47). No excess risks were found for other causes of death. Socially isolated men were also at increased risk of stroke incidence (relative risk, 2.21; 95% CI, 1.12, 4.35), but not incidence of non-fatal myocardial infarction. CONCLUSIONS: Social networks were associated with lower total mortality by reducing deaths from cardiovascular disease and accidents/suicides. Strong social networks were associated with reduced incidence of stroke, though not of coronary heart disease. However, social networks may assist in prolonging the survival of men with established coronary heart disease.
PMCID: PMC1060278  PMID: 8935453
15.  Cardiorespiratory Fitness as a Predictor of Nonfatal Cardiovascular Events in Asymptomatic Women and Men 
American journal of epidemiology  2007;165(12):1413-1423.
Prospective data relating cardiorespiratory fitness (CRF) with nonfatal cardiovascular disease (CVD) events are limited to studies in men or studies of combined fatal and nonfatal CVD endpoints. The authors examined the association between CRF and nonfatal CVD events in 20,728 men and 5,909 women without CVD at baseline. All participants performed a maximal treadmill exercise test and completed a follow-up health survey in the Aerobics Center Longitudinal Study (Dallas, Texas) between 1971 and 2004. There were 1,512 events in men and 159 events in women during an average follow-up of 10 years. Across incremental CRF groups, age- and examination year-adjusted event rates per 10,000 person-years were 107.9, 75.2, and 50.3 in men (p trend <0.001) and 41.9, 27.7, and 20.8 in women (p trend = 0.002). After further adjustment for smoking, alcohol intake, family history of CVD, and abnormal exercise ECG responses, hazard ratios (95% confidence interval) were 1.00 (referent), 0.82 (0.72, 0.94), and 0.61 (0.53, 0.71) in men, p trend <0.001, and were 1.00 (referent), 0.74 (0.49, 1.13), and 0.63 (0.40, 0.98) in women, p trend = 0.05. After adjustment for other CVD predictors, the association remained significant in men but not in women.
PMCID: PMC2685148  PMID: 17406007
exercise; cardiovascular diseases; stroke; women; primary prevention
16.  The Obesity Paradox, Cardiorespiratory Fitness, and Coronary Heart Disease 
Mayo Clinic Proceedings  2012;87(5):443-451.
To investigate associations of cardiorespiratory fitness (CRF) and different measures of adiposity with cardiovascular disease (CVD) and all-cause mortality in men with known or suspected coronary heart disease (CHD).
Patients and Methods
We analyzed data from 9563 men (mean age, 47.4 years) with documented or suspected CHD in the Aerobics Center Longitudinal Study (August 13, 1977, to December 30, 2002) using baseline body mass index (BMI) and CRF (quantified as the duration of a symptom-limited maximal treadmill exercise test). Waist circumference (WC) and percent body fat (BF) were measured using standard procedures.
There were 733 deaths (348 of CVD) during a mean follow-up of 13.4 years. After adjustment for age, examination year, and multiple baseline risk factors, men with low fitness had a higher risk of all-cause mortality in the BMI categories of normal weight (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.24-2.05), obese class I (HR, 1.38; 95% CI, 1.04-1.82), and obese class II/III (HR, 2.43; 95% CI, 1.55-3.80) but not overweight (HR, 1.09; 95% CI, 0.88-1.36) compared with the normal-weight and high-fitness reference group. We observed a similar pattern for WC and percent BF tertiles and for CVD mortality. Among men with high fitness, there were no significant differences in CVD and all-cause mortality risk across BMI, WC, and percent BF categories.
In men with documented or suspected CHD, CRF greatly modifies the relation of adiposity to mortality. Using adiposity to assess mortality risk in patients with CHD may be misleading unless fitness is considered.
PMCID: PMC3538467  PMID: 22503065
ACLS, Aerobics Center Longitudinal Study; BF, body fat; BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; CRF, cardiorespiratory fitness; CVD, cardiovascular disease; DM, diabetes mellitus; HR, hazard ratio; HTN, hypertension; WC, waist circumference
17.  Cardiorespiratory fitness and digestive cancer mortality: findings from the Aerobics Center Longitudinal Study (ACLS) 
Although higher levels of physical activity are inversely associated with risk of colon cancer, few prospective studies have evaluated overall digestive system cancer mortality in relation to cardiorespiratory fitness (CRF). The authors examined this association among 38,801 men aged 20−88 years and who performed a maximal treadmill exercise test at baseline in the Aerobics Center Longitudinal Study (Dallas, Texas) during 1974−2003. Mortality was assessed over 29 years of follow-up (1974−2003). 283 digestive system cancer deaths occurred during a mean 17-year of observation. Age-adjusted mortality rates per 10,000 person-yrs according to low, moderate, and high CRF groups were 6.8, 4.0, and 3.3 for digestive system cancer (trend p < 0.001). After adjustment for age, examination year, body mass index, smoking, drinking, family history of cancer, personal history of diabetes, hazard ratios for overall digestive cancer deaths (95% confidence interval) for those in the middle and upper 40% of the distribution of CRF relative to those in the lowest 20% were 0.66 (0.49, 0.88) and 0.56 (0.40, 0.80), respectively. Being fit (the upper 80% of CRF) was associated with a lower risk of mortality from colon (0.61 [0.37, 1.00]), colorectal (0.58 [0.37, 0.92]), and liver cancer (0.28 [0.11, 0.72]), compared with being unfit (the lowest 20% of CRF). These findings support a protective role of CRF against total digestive tract, colorectal, and liver cancer deaths in men.
PMCID: PMC2688961  PMID: 19293313
exercise; primary prevention; cohort study; digestive cancer mortality; men
18.  The Joint Effect of Sleep Duration and Disturbed Sleep on Cause-Specific Mortality: Results from the Whitehall II Cohort Study 
PLoS ONE  2014;9(4):e91965.
Both sleep duration and sleep quality are related to future health, but their combined effects on mortality are unsettled. We aimed to examine the individual and joint effects of sleep duration and sleep disturbances on cause-specific mortality in a large prospective cohort study.
We included 9,098 men and women free of pre-existing disease from the Whitehall II study, UK. Sleep measures were self-reported at baseline (1985–1988). Participants were followed until 2010 in a nationwide death register for total and cause-specific (cardiovascular disease, cancer and other) mortality.
There were 804 deaths over a mean 22 year follow-up period. In men, short sleep (≤6 hrs/night) and disturbed sleep were not independently associated with CVD mortality, but there was an indication of higher risk among men who experienced both (HR = 1.57; 95% CI: 0.96–2.58). In women, short sleep and disturbed sleep were independently associated with CVD mortality, and women with both short and disturbed sleep experienced a much higher risk of CVD mortality (3.19; 1.52–6.72) compared to those who slept 7–8 hours with no sleep disturbances; equivalent to approximately 90 additional deaths per 100,000 person years. Sleep was not associated with death due to cancer or other causes.
Both short sleep and disturbed sleep are independent risk factors for CVD mortality in women and future studies on sleep may benefit from assessing disturbed sleep in addition to sleep duration in order to capture health-relevant features of inadequate sleep.
PMCID: PMC3974730  PMID: 24699341
19.  Maximal Exercise Electrocardiography Responses and Coronary Heart Disease Mortality Among Men With Diabetes Mellitus 
Circulation  2008;117(21):2734-2742.
An abnormal ECG during maximal exercise testing has been shown to be a powerful predictor of future coronary heart disease (CHD) mortality in asymptomatic men. However, little is known about the relationship between exercise ECG responses and CHD risk in men with diabetes mellitus.
Methods and Results
We examined the association between exercise ECG responses and mortality in 2854 men with documented diabetes mellitus (mean age 49.5 years) who completed a maximal treadmill exercise test during the period from 1974 to 2001 and who were without a previous cardiovascular disease (CVD) event at baseline. Mortality due to all causes, CHD, and CVD were the main outcome measures across categories of exercise ECG responses, with stratification by cardiorespiratory fitness, quantified as treadmill test duration. During an average follow-up of 16 years, 441 deaths (210 CVD and 133 CHD) were identified. Across normal, equivocal, and abnormal exercise ECG groups, age- and examination year-adjusted CHD mortality rates per 10 000 person-years were 23.0, 48.6, and 69.0, respectively (Ptrend<0.001). After further adjustment for fasting plasma glucose level, smoking, body mass index, hypercholesterolemia, hypertension, family history of CVD or diabetes mellitus, abnormal resting ECG responses, and cardiorespiratory fitness, hazard ratios (95% confidence intervals) were 1.00 (referent), 1.68 (1.01 to 2.77), and 2.21 (1.41 to 3.46; Ptrend<0.001). Similar patterns of associations were noted between exercise ECG testing and both CVD and all-cause mortality risk.
Among men with diabetes mellitus, equivocal and abnormal exercise ECG responses were associated with higher risk of all-cause, CVD, and CHD mortality.
PMCID: PMC2875671  PMID: 18490521
exercise; electrocardiography; coronary disease; diabetes mellitus
20.  Adult height and mortality in London: early life, socioeconomic confounding, or shrinkage? 
STUDY OBJECTIVE--To examine in detail the cause specific associations between height and mortality. DESIGN--A prospective cohort study with an 18 year mortality follow up. SETTING AND PARTICIPANTS--The Whitehall study of 18,403 men in the civil service in London examined between 1967 and 1969 aged 40-64 and followed up for mortality until the end of January 1987. MAIN RESULTS--There was considerable variation in the strength of height-mortality association by cause. Respiratory disease showed the strongest inverse association, cardiovascular disease a moderate effect, and all neoplasms virtually no effect. Adjustment for age and civil service grade reduced the strength of these associations slightly, but had no impact on the heterogeneous pattern by cause (chi 2 3df p < 0.001). The height-mortality association declined with the length of follow up. By 15+ years, the only appreciable height affect was for respiratory disease mortality. CONCLUSIONS--The attenuation of the height-mortality association with length of follow up might be explained by differential height reduction before entry that was greatest for people who were already ill, and hence at greatest risk of dying. The cause specific variation in the height-mortality association lends little support to the contention that impaired growth in childhood is a marker of general susceptibility to disease in adulthood.
PMCID: PMC1060066  PMID: 7707006
21.  The Influence of Cardiorespiratory Fitness on Lung Cancer Mortality 
Previous studies have suggested that higher levels of physical activity may lower lung cancer risk; however, few prospective studies have evaluated lung cancer mortality in relation to cardiorespiratory fitness (CRF), an objective marker of recent physical activity habits.
Thirty-eight thousand men, aged 20 to 84 years without history of cancer, received a preventive medical examination at the Cooper Clinic in Dallas, TX, between 1974 and 2002. CRF was quantified as maximal treadmill exercise test duration and was grouped for analysis as low (lowest 20% of exercise duration), moderate (middle 40%), and high (upper 40%).
A total of 232 lung cancer deaths occurred during follow-up (mean=17 years). After adjustment for age, examination year, BMI, smoking, drinking, physical activity, and family history of cancer, hazard ratios (95% confidence intervals) for lung cancer deaths across low, moderate and high CRF categories were: 1.0, 0.48 (0.35–0.67), and 0.43 (0.28–0.65) respectively. There was an inverse association between CRF and lung cancer mortality in former (P for trend = 0.005) and current smokers (P for trend <0.001), but not in never smokers (trend P = 0.14). Joint analysis of smoking and fitness status revealed a significant 12-fold higher risk of death in current smokers (HR: 11.9; 95% CI: 6.0–23.6) with low CRF as compared with never smokers who had high CRF.
Although the potential for some residual confounding by smoking could not be eliminated, these data suggest that CRF is inversely associated with lung cancer mortality in men. Continued study of CRF in relation to lung cancer, particularly among smokers, may further our understanding of disease etiology and reveal additional strategies for reducing its burden.
PMCID: PMC2859116  PMID: 19996990
Death from lung cancer; physical activity; smoking; prevention; epidemiology
22.  Relationships between insulin sensitivity, skeletal muscle mass and muscle quality in obese adolescent boys 
European journal of clinical nutrition  2012;66(12):10.1038/ejcn.2012.142.
We examined the relationships between insulin sensitivity (IS), skeletal muscle (SM) mass and SM quality in youth. Forty obese adolescent boys (body mass index ≥95th percentile, 12–18 years) participated in this study. IS and glucose tolerance was measured by a 3 h hyperinsulinemic–euglycemic clamp and a 2 h oral glucose tolerance test (OGTT), total SM mass and intermusular adipose tissue (IMAT) by whole-body magnetic resonance imaging, and muscular strength by one-repetition maximum leg and bench press. IMAT was associated (P<0.05) with IS (r= −0.53) and OGTT-insulin area under the curve (AUC; r=0.31). Similarly, muscular strength was associated (P<0.05) with both IS (r=0.39) and OGTT-insulin AUC (r= −0.32). By contrast, total SM mass was not associated with IS or any OGTT parameters (P>0.1). After accounting for race and tanner stage, IMAT and muscular strength remained significantly associated with IS, together explaining a total of 41% of the variance in IS. Our findings suggest that SM quality, but not SM mass, is associated with IS in obese adolescent boys.
PMCID: PMC3656505  PMID: 23073260
SM mass; intermuscular adipose tissue; muscular strength; IS; childhood obesity
23.  Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study 
BMJ Open  2012;2(2):e000866.
To evaluate the association between restless legs syndrome (RLS) and incident cardiovascular disease (CVD).
Prospective cohort study.
Women's Health Study (WHS) and Physicians' Health Study (PHS), USA.
29 756 female health professionals aged ≥45 years and 19 182 male physicians aged ≥40 years at baseline.
Main outcome measures
Main outcome was incidence of major CVD; secondary outcomes were first incidence of myocardial infarction, stroke, death due to CVD or coronary revascularisation.
3487 (11.7%) women and 1373 (7.2%) men met International Restless Legs Study Group criteria for RLS. In the WHS 450 major CVD events occurred and 1064 major CVD events were confirmed in the PHS. In both cohorts, RLS was not associated with increased risk of major CVD, stroke, myocardial infarction, CVD death or coronary revascularisation. After adjustment for major vascular risk factors, the HRs (95% CI) for major CVD were 1.15 (0.88 to 1.50) in women and 1.01 (0.81 to 1.25) in men. Highest multivariable-adjusted HRs were 1.29 (0.91 to 1.82) for total stroke in women and 1.22 (0.87 to 1.70) for CVD death in men. Excluding participants with comorbidities potentially leading to RLS did not substantially change the effect estimates.
In these large prospective studies of female and male health professionals, RLS was not associated with an increased risk of any incident CVD event. The data do not support the hypothesis that RLS is a marker of increased risk of vascular disease.
Article summary
Article focus
The aim of this study is to evaluate the association between RLS and incident cardiovascular events in two large prospective cohort studies.
Key messages
The results of our two large prospective cohorts do not suggest that either women or men suffering from RLS are at increased risk for any vascular disease event.
RLS should not be considered a marker for increased CVD risk.
Strengths and limitations of this study
Strengths of this study include the large number of participants and outcome events, the prospective study design, the standardised assessment of RLS according to the four minimal diagnostic criteria and confirmation of CVD cases by medical record review.
The following limitations should be considered: the information on RLS was self-reported and misclassification of cases is possible. No information on frequency, severity and duration of RLS symptoms was available and both cohorts consist of white health professionals, which may limit the generalisability of the results to other populations.
PMCID: PMC3312075  PMID: 22447047
24.  Systemic Vascular Function Is Associated with Muscular Power in Older Adults 
Journal of Aging Research  2012;2012:386387.
Age-associated loss of muscular strength and muscular power is a critical determinant of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measures of vascular endothelial function included brachial artery flow-mediated dilation (FMD) and the pulse wave amplitude reactive hyperemia index (PWA-RHI). Augmentation index (AIx) was taken as a measure of systemic vascular function related to arterial stiffness and wave reflection. Measures of muscular strength included one repetition maximum (1RM) for a bilateral leg press. Peak muscular power was measured during 5 repetitions performed as fast as possible for bilateral leg press at 40% 1RM. Muscular power was associated with brachial FMD (r = 0.43, P < 0.05), PWA-RHI (r = 0.42, P < 0.05), and AIx (r = −0.54, P < 0.05). Muscular strength was not associated with any measure of vascular function. In conclusion, systemic vascular function is associated with lower-limb muscular power but not muscular strength in older adults. Whether loss of muscular power with aging contributes to systemic vascular deconditioning or vascular dysfunction contributes to decrements in muscular power remains to be determined.
PMCID: PMC3433136  PMID: 22966457
25.  Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk) 
BMJ : British Medical Journal  2001;322(7277):15.
To examine the value of glycated haemoglobin (HbA1c) concentration, a marker of blood glucose concentration, as a predictor of death from cardiovascular and all causes in men.
Prospective population study.
Norfolk cohort of European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk).
4662 men aged 45-79 years who had had glycated haemoglobin measured at the baseline survey in 1995-7 who were followed up to December 1999.
Main outcome measures
Mortality from all causes, cardiovascular disease, ischaemic heart disease, and other causes.
Men with known diabetes had increased mortality from all causes, cardiovascular disease, and ischaemic disease (relative risks 2.2, 3.3, and 4.2, respectively, P <0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by HbA1c concentration. HbA1c was continuously related to subsequent all cause, cardiovascular, and ischaemic heart disease mortality through the whole population distribution, with lowest rates in those with HbA1c concentrations below 5%. An increase of 1% in HbA1c was associated with a 28% (P<0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking habit; this effect remained (relative risk 1.46, P=0.05 adjusted for age and risk factors) after men with known diabetes, a HbA1c concentration ⩾7%, or history of myocardial infarction or stroke were excluded. 18% of the population excess mortality risk associated with a HbA1c concentration ⩾5% occurred in men with diabetes, but 82% occurred in men with concentrations of 5%-6.9% (the majority of the population).
Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution. Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA1c through behavioural means.
PMCID: PMC26599  PMID: 11141143

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