Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m² increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10⁻¹⁰). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10⁻⁸) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10⁻⁸). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10⁻⁷). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.     

Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2

Objective To develop and validate version two of the QRISK cardiovascular disease risk algorithm (QRISK2) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in England and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence (NICE).Design Prospective open cohort study with routinely collected data from general practice, 1 January 1993 to 31 March 2008.Setting 531 practices in England and Wales contributing to the national QRESEARCH database.Participants 2.3 million patients aged 35-74 (over 16 million person years) with 140 000 cardiovascular events. Overall population (derivation and validation cohorts) comprised 2.22 million people who were white or whose ethnic group was not recorded, 22 013 south Asian, 11 595 black African, 10 402 black Caribbean, and 19 792 from Chinese or other Asian or other ethnic groups.Main outcome measures First (incident) diagnosis of cardiovascular disease (coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records or linked Office for National Statistics death certificates. Risk factors included self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 2 diabetes, renal disease, atrial fibrillation, and rheumatoid arthritis.Results The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score. The QRISK2 algorithm explained 43% of the variation in women and 38% in men compared with 39% and 35%, respectively, by the modified Framingham score. Of the 112 156 patients classified as high risk (that is, ≥20% risk over 10 years) by the modified Framingham score, 46 094 (41.1%) would be reclassified at low risk with QRISK2. The 10 year observed risk among these reclassified patients was 16.6% (95% confidence interval 16.1% to 17.0%)—that is, below the 20% treatment threshold. Of the 78 024 patients classified at high risk on QRISK2, 11 962 (15.3%) would be reclassified at low risk by the modified Framingham score. The 10 year observed risk among these patients was 23.3% (22.2% to 24.4%)—that is, above the 20% threshold. In the validation cohort, the annual incidence rate of cardiovascular events among those with a QRISK2 score of ≥20% was 30.6 per 1000 person years (29.8 to 31.5) for women and 32.5 per 1000 person years (31.9 to 33.1) for men. The corresponding figures for the modified Framingham equation were 25.7 per 1000 person years (25.0 to 26.3) for women and 26.4 (26.0 to 26.8) for men). At the 20% threshold, the population identified by QRISK2 was at higher risk of a CV event than the population identified by the Framingham score.Conclusions Incorporating ethnicity, deprivation, and other clinical conditions into the QRISK2 algorithm for risk of cardiovascular disease improves the accuracy of identification of those at high risk in a nationally representative population. At the 20% threshold, QRISK2 is likely to be a more efficient and equitable tool for treatment decisions for the primary prevention of cardiovascular disease. As the validation was performed in a similar population to the population from which the algorithm was derived, it potentially has a “home advantage.” Further validation in other populations is therefore advised.     

Association between muscular strength and mortality in men: prospective cohort study

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.     

High atherogenic index of plasma and cardiovascular risk factors among Ghanaian breast cancer patients

Comorbidities impact negatively on breast cancer prognosis, especially in developing countries where cases are usually presented to clinics at advanced stages. This study aimed to determine the atherogenic index of plasma (AIP) and cardiovascular risk factors among Ghanaian women diagnosed with breast cancer. A total of 52 breast cancer patients were age-matched with 52 healthy controls. Sociodemographics of participants were obtained using a well-structured questionnaire. Pathological data of patients were obtained from medical records, and all clinical and anthropometric measurements were done using standard instruments. Lipid profile was determined from serum using enzymatic assays, and cardiovascular risk factors were calculated from estimated lipid parameters. Blood pressure, AIP, total cholesterol (T. chol), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) were significantly elevated (P < 0.05) in the breast cancer patients compared to the controls, but the reverse was observed for high-density lipoprotein cholesterol (HDL-c) (P < 0.01). Obesity (odds ratio [OR] = 2.51, P = 0.015), hypertension (OR = 4.04, P < 0.001), AIP (OR = 10.44, P < 0.001), and dyslipidemia (P < 0.01) were significantly associated with breast cancer. AIP correlated positively with age (r = 0.244, P < 0.05), body mass index (r = 0.225, P < 0.05), blood pressure (P < 0.01), T. chol (r =0.418, P< 0.01), and TG (r = 0.880, P < 0.01), but inversely correlated with HDL-c (r = −0.460, P < 0.01). A greater proportion (88%) of the patients presented with advanced breast cancer. AIP and cardiovascular risk factors were high in the breast cancer patients. Considering that AIP and cardiovascular disease risk factors are of interest in breast cancer patients, further studies are needed to understand the effect of AIP and cardiovascular risk factors on breast cancer outcomes.     

Non-fasting serum triglyceride concentration and mortality from coronary heart disease and any cause in middle aged Norwegian women.

OBJECTIVE--To study the association between non-fasting serum triglyceride concentrations and mortality in women from coronary and cardiovascular disease and all causes. DESIGN--Follow up by ambulatory teams of men and women who underwent cardiovascular screening for a mean of 14.6 years. SETTING--National health screening service in Norway. SUBJECTS--25,058 men and 24,535 women aged 35-49 years. MAIN OUTCOME MEASURE--Predictive value of non-fasting serum triglyceride concentrations. RESULTS--At initial screening total serum cholesterol concentration, serum triglyceride concentration, blood pressure, height, and weight were measured, and self reported information about smoking habits, physical activity, and time since last meal were recorded. During subsequent follow up 108 women died from coronary heart disease, 238 from cardiovascular diseases, and 931 from all causes. In women mortality increased steadily with increasing triglyceride concentration for all three causes of death. With the proportional hazards model and adjustment for age, systolic blood pressure, total cholesterol concentration, time since last meal, and number of cigarettes a day the relative risk between triglyceride concentration > or = 3.5 mmol/l and < 1.5 mmol/l was 4.7 (95% confidence interval 2.5 to 8.9) for deaths from coronary heart disease, 3.0 (1.9 to 4.8) for deaths from cardiovascular disease, 2.3 (1.8 to 2.9) for total deaths in all women. CONCLUSIONS--A raised non-fasting concentration of triglycerides is an independent risk factor for mortality from coronary heart disease, cardiovascular disease, and any cause mortality among middle aged Norwegian women in contrast to what is seen in men.     

Pre-Eclampsia Increases the Risk of Postpartum Haemorrhage: A Nationwide Cohort Study in The Netherlands

Background

Postpartum haemorrhage is a leading cause of maternal morbidity and mortality worldwide. Identifying risk indicators for postpartum haemorrhage is crucial to predict this life threatening condition. Another major contributor to maternal morbidity and mortality is pre-eclampsia. Previous studies show conflicting results in the association between pre-eclampsia and postpartum haemorrhage. The primary objective of this study was to investigate the association between pre-eclampsia and postpartum haemorrhage. Our secondary objective was to identify other risk indicators for postpartum haemorrhage in the Netherlands.

Methods

A nationwide cohort was used, containing prospectively collected data of women giving birth after 19 completed weeks of gestation from January 2000 until January 2008 (n =  1 457 576). Data were extracted from the Netherlands Perinatal Registry, covering 96% of all deliveries in the Netherlands. The main outcome measure, postpartum haemorrhage, was defined as blood loss of ≥1000 ml in the 24 hours following delivery. The association between pre-eclampsia and postpartum haemorrhage was investigated with uni- and multivariable logistic regression analyses.

Results

Overall prevalence of postpartum haemorrhage was 4.3% and of pre-eclampsia 2.2%. From the 31 560 women with pre-eclampsia 2 347 (7.4%) developed postpartum haemorrhage, compared to 60 517 (4.2%) from the 1 426 016 women without pre-eclampsia (odds ratio 1.81; 95% CI 1.74 to 1.89). Risk of postpartum haemorrhage in women with pre-eclampsia remained increased after adjusting for confounders (adjusted odds ratio 1.53; 95% CI 1.46 to 1.60).

Conclusion

Women with pre-eclampsia have a 1.53 fold increased risk for postpartum haemorrhage. Clinicians should be aware of this and use this knowledge in the management of pre-eclampsia and the third stage of labour in order to reach the fifth Millenium Developmental Goal of reducing maternal mortality ratios with 75% by 2015.     

Red Meat and Poultry Intakes and Risk of Total and Cause-Specific Mortality: Results from Cohort Studies of Chinese Adults in Shanghai

Most previous studies of meat intake and total or cause-specific mortality were conducted in North America, whereas studies in other areas have been limited and reported inconsistent results. This study investigated the association of red meat or poultry intake with risk of total and cause-specific mortality, including cancer and cardiovascular disease (CVD), in two large population-based prospective cohort studies of 134,290 Chinese adult women and men in Shanghai. Meat intakes were assessed through validated food frequency questionnaires administered in person at baseline. Vital status and dates and causes of deaths were ascertained through annual linkage to the Shanghai Vital Statistics Registry and Shanghai Cancer Registry databases and home visits every 2–3 years. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of death associated with quintiles of meat intake. During 803,265 person-years of follow up for women and 334,281 person-years of follow up for men, a total of 4,210 deaths in women and 2,733 deaths in men accrued. The median intakes of red meat were 43 g/day among women and 54 g/day among men, and pork constituted at least 95% of total meat intake for both women and men. Red meat intake was associated with increased total mortality among men, but not among women; the HR (95% CI) comparing the highest with the lowest quintiles were 1.18 (1.02–1.35) and 0.92 (0.82–1.03), respectively. This sex difference was statistically significant (P = 0.01). Red meat intake was associated with increased risk of ischemic heart disease mortality (HR = 1.41, 95% CI = 1.05–1.89) and with decreased risk of hemorrhagic stroke mortality (HR = 0.62, 95% CI = 0.45–0.87). There were suggestive inverse associations of poultry intake with risk of total and all-CVD mortality among men, but not among women. Further investigations are needed to elucidate the sex-specific associations between red meat intake and mortality.     

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.     

Relationship between adult height and body weight and risk of carotid atherosclerosis assessed in terms of carotid intima-media thickness: The Nagasaki Islands study

Background

Previous studies have reported an inverse association between height and risk of cardiovascular disease. However, evidence is limited for the association between risk of atherosclerosis and height. Further, although the association between atherosclerosis and body mass index (BMI) is reportedly positive, there have been no reports of studies on associations between height and atherosclerosis in relation to BMI.

Methods

We conducted a cross-sectional study of Japanese men aged 30 to 89 years undergoing general health check-ups.

Results

Of the 1,337 men, 312 were diagnosed with carotid atherosclerosis (carotid intima-media thickness (CIMT) ≥ 1.1 mm), but no significant association was found between height and carotid atherosclerosis for the entire study group. Stratification by BMI status of those analytical findings disclosed a significant inverse association between height and carotid atherosclerosis among overweight (BMI ≥ 25 kg/m²) but not among non-overweight (BMI < 25 kg/m²) men. The classical cardiovascular risk factors-adjusted odds ratio (OR) and 95% confidence interval (CI) of carotid atherosclerosis for an increment of one SD (standard deviation) in height (6.70 cm) were 0.71 (0.54 to 0.94) for overweight (BMI ≥ 25 kg/m²) and 1.05 (0.87 to 1.27) for non-overweight (BMI < 25 kg/m²) men.

Conclusion

Independent from classical cardiovascular risk factors, height was found to be inversely associated with carotid atherosclerosis for overweight but not for non-overweight men.     

Body Mass Index and Mortality in the General Population and in Subjects with Chronic Disease in Korea: A Nationwide Cohort Study (2002-2010)

Background

The association between body mass index (BMI) and mortality is not conclusive, especially in East Asian populations. Furthermore, the association has been neither supported by recent data, nor assessed after controlling for weight changes.

Methods

We evaluated the relationship between BMI and all-cause or cause-specific mortality, using prospective cohort data by the National Health Insurance Service in Korea, which consisted of more than one million subjects. A total of 153,484 Korean adults over 30 years of age without pre-existing cardiovascular disease or cancer at baseline were followed-up until 2010 (mean follow-up period = 7.91 ± 0.59 years). Study subjects repeatedly measured body weight 3.99 times, on average.

Results

During follow-up, 3,937 total deaths occurred; 557 deaths from cardiovascular disease, and 1,224 from cancer. In multiple-adjusted analyses, U-shaped associations were found between BMI and mortality from any cause, cardiovascular disease, and cancer after adjustment for age, sex, smoking status, alcohol consumption, physical activity, socioeconomic status, and weight change. Subjects with a BMI < 23 kg/m² and ≥ 30 kg/m² had higher risks of all-cause and cause-specific mortality compared with the reference group (BMI 23–24.9 kg/m²). The lowest risk of all-cause mortality was observed in subjects with a BMI of 25–26.4 kg/m² (adjusted hazard ratio [HR] 0.86; 95% CI 0.77 to 0.97). In subgroup analyses, including the elderly and those with chronic diseases (diabetes mellitus, hypertension, and chronic kidney disease), subjects with a BMI of 25–29.9 kg/m² (moderate obesity) had a lower risk of mortality compared with the reference. However, this association has been attenuated in younger individuals, in those with higher socioeconomic status, and those without chronic diseases.

Conclusion

Moderate obesity was associated more strongly with a lower risk of mortality than with normal, underweight, and overweight groups in the general population of South Korea. This obesity paradox was prominent in not only the elderly but also individuals with chronic disease.     

Menopausal Hormone Therapy and Lung Cancer-Specific Mortality Following Diagnosis: The California Teachers Study

Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52–0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35–0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38–0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.     

A Prospective Cohort Study Examining the Associations of Dietary Calcium Intake with All-Cause and Cardiovascular Mortality in Older Chinese Community-Dwelling People

Background

Most epidemiological studies of calcium intake and mortality risk have been conducted in populations with moderate to high calcium intake, and limited studies have focused on populations with low habitual calcium intake (i.e., mean dietary calcium intake <700 mg/d).

Objective

This study investigated the association between dietary calcium intake and death from all causes and cardiovascular disease in Chinese population with low habitual calcium intake.

Design

Data from 3,139 Chinese men and women in a population-based prospective cohort study, aged >=65 years and free of heart diseases or stroke at baseline, were analyzed. Primary outcome measures, identified from the death registry, were death from all causes and cardiovascular disease. Dietary calcium intake assessed using a validated food frequency questionnaire was categorized into sex-specific quartiles. Data on use of supplemental calcium (yes or no) including individual calcium supplements and other calcium containing supplement were collected. Cox regression models adjusted for demographic and lifestyle variables were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI).

Results

During a median of 9.1 years of follow-up, 529 all-cause deaths (344 men, 185 women) and 114 (74 men, 40 women) deaths from cardiovascular disease were identified. An inverse trend between dietary calcium intake and mortality was observed. Compared with the lowest quartile (<458 mg/d for men, <417 mg/d for women), the highest quartile of dietary calcium intake (>762 mg/d for men, >688 mg/d for women) had a significantly reduced risk of all-cause mortality (multivariate HR=0.63, 95% CI=0.49-0.81, P _trend<0.001) but an insignificant decreased risk of cardiovascular mortality (multivariate HR=0.70, 95% CI=0.41-1.21, P _trend=0.228). Similar inverse association was observed when the analyses were stratified on calcium supplemental use.

Conclusions

Higher intake of dietary calcium was associated with reduced risk of all-cause mortality and possibly cardiovascular mortality in Chinese older people with low habitual calcium intake.     

Change in Body Size and Mortality: Results from the Melbourne Collaborative Cohort Study

Background

The association between change in weight or body mass index, and mortality is widely reported, however, both measures fail to account for fat distribution. Change in waist circumference, a measure of central adiposity, in relation to mortality has not been studied extensively.

Methods

We investigated the association between mortality and changes in directly measured waist circumference, hips circumference and weight from baseline (1990–1994) to wave 2 (2003–2007) in a prospective cohort study of people aged 40–69 years at baseline. Cox regression, with age as the time metric and follow-up starting at wave 2, adjusted for confounding variables, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for change in body size in relation to mortality from all causes, cardiovascular disease and cancer.

Results

There were 1465 deaths (109 cancer, 242 cardiovascular disease) identified during an average 7.7 years of follow-up from 21 298 participants. Compared to minimal increase in body size, loss of waist circumference (HR: 1.26; 95% CI: 1.09–1.47), weight (1.80; 1.54–2.11), or hips circumference (1.35; 1.15–1.57) were associated with an increased risk of all-cause mortality, particularly for older adults. Weight loss was associated with cardiovascular disease mortality (2.40; 1.57–3.65) but change in body size was not associated with obesity-related cancer mortality.

Conclusion

This study confirms the association between weight loss and increased mortality from all-causes for older adults. Based on evidence from observational cohort studies, weight stability may be the recommended option for most adults, especially older adults.     

Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study

Background

Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.

Methods and Findings

We used data from the Shanghai Women''s Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996–2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse''s smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44–0.74) for total mortality, 0.29 (0.16–0.54) for CVD mortality, and 0.76 (0.54–1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4–5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.

Conclusions

In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern—including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake—was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention. Please see later in the article for the Editors'' Summary     

The Joint Effect of Sleep Duration and Disturbed Sleep on Cause-Specific Mortality: Results from the Whitehall II Cohort Study

Background

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.

Methods

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.

Results

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.

Conclusion

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.     

Mortality Associated with Diabetes and Cardiovascular Disease in Older Women

Background

Current guidelines for the prevention of cardiovascular disease (CVD) recommend diabetes as a CVD risk equivalent. However, reports that have examined the risk of diabetes in comparison to pre-existing CVD are lacking among older women. We aimed to assess whether diabetes was associated with a similar risk of total and cause-specific mortality as a history of CVD in older women.

Methodology/Principal Findings

We studied 9218 women aged 68 years or older enrolled in a prospective cohort study (Study of Osteoporotic Fracture) during a mean follow-up period of 11.7 years and compared all-cause, cardiovascular and coronary heart disease mortality among 4 groups: non-diabetic women with and without existing CVD, diabetic women with and without existing CVD. Mean (SD) age of the participants was 75.2 (5.3) years, 3.5% reported diabetes and 6.8% reported existing CVD. During follow-up, 5117 women died with 36% from CVD. The multivariate adjusted risk of cardiovascular mortality was increased among both non-diabetic women with CVD (hazard ratio (HR) 2.32, 95% CI: 1.97–2.74, P<0.001) and diabetic women without CVD (HR 2.06, CI: 1.62–2.64, P<0.001) compared to non-diabetic women without existing CVD. All-cause, cardiovascular and coronary mortality of non-diabetic women with CVD were not significantly different from diabetic women without CVD.

Conclusions/Significance

Older diabetic women without CVD have a similar risk of cardiovascular mortality compared to non-diabetic women with pre-existing CVD. The equivalence of diabetes and CVD seems to extend to older women, supporting current guidelines for cardiovascular prevention.     

Reduced Heart Rate Variability and Altered Cardiac Conduction after Pre-Eclampsia

Pre-eclampsia is a hypertensive disorder of pregnancy that is associated with elevated maternal risk for cardiovascular disease. The aims of this study were to determine the effect of normal pregnancy on postpartum parameters of the electrocardiogram, and furthermore to determine how a history of pre-eclampsia may affect these parameters. Ten-minute high-resolution (1000 Hz) orthogonal Holter electrocardiogram (ECG) recordings were used to measure heart rate variability (HRV). Signal-averaged P-wave and QRS complex durations were determined. Participants included non-pregnant controls, normotensive parous controls and women with a recent history of PE. While reductions in HRV induced by uncomplicated pregnancy returned to non-pregnant levels by 6–8 months postpartum HRV remained reduced in women with a history of PE compared to control groups. In addition, P-Wave and QRS complex durations were prolonged in PE subjects at 6–8 months postpartum compared to control groups. Only QRS duration was independent of differences in blood pressure. These results suggest increased sympathetic cardiac activity, and delayed myocardial conduction in women after PE; alterations consistent with cardiac remodeling and increased risk for arrhythmia. In examining the association between PE and cardiovascular disease, identification of ECG abnormalities soon after pregnancy in women with a history of PE highlights a unique opportunity for early identification and screening in this population before other risk factors become apparent.     

Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study

Objective To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3.Design Prospective cohort study.Setting Swedish cancer registry.Participants All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132 493) contributing 2 315 724 woman years.Main outcome measures Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references.Results Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results.Conclusions Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.     

Calcium Intake and Serum Concentration in Relation to Risk of Cardiovascular Death in NHANES III

Background

Evidence for an association between calcium intake and risk of cardiovascular death remains controversial. By assessing dietary intake, use of supplements, and serum levels of calcium, we aimed to disentangle this link in the third National Health and Nutrition Examination Survey (NHANES III).

Methods

Mortality linkage of NHANES III to death certificate data for those aged 17 years or older (n = 20,024) was used to estimate risk of overall cardiovascular death as well as death from ischemic heart disease (IHD), acute myocardial infarction (AMI), heart failure (HF), and cerebrovascular disease (CD) with multivariate Cox proportional hazards regression analysis.

Results

About 10.0% of the population died of cardiovascular disease and the majority (5.4%) died of IHD. There was increased risk of overall CVD death for those in the bottom 5% of serum calcium compared to those in the mid 90% (HR: 1.51 (95% CI: 1.03–2.22)). For women there was a statistically significant increased risk of IHD death for those with serum calcium levels in the top 5% compared to those in the mid 90% (HR: 1.72 (95%CI: 1.13–2.61)), whereas in men, low serum calcium was related to increased IHD mortality (HR: 2.32 (95% CI 1.14–3.01), P_interaction: 0.306). No clear association with CVD death was observed for dietary or supplemental calcium intake.

Conclusions

Calcium as assessed by serum concentrations is involved in cardiovascular health, though differential effects by sex may exist. No clear evidence was found for an association between dietary or supplementary intake of calcium and cardiovascular death.     

Obesity Indexes and Total Mortality among Elderly Subjects at High Cardiovascular Risk: The PREDIMED Study

Background

Different indexes of regional adiposity have been proposed for identifying persons at higher risk of death. Studies specifically assessing these indexes in large cohorts are scarce. It would also be interesting to know whether a dietary intervention may counterbalance the adverse effects of adiposity on mortality.

Methods

We assessed the association of four different anthropometric indexes (waist-to-height ratio (WHtR), waist circumference (WC), body mass index (BMI) and height) with all-cause mortality in 7447 participants at high cardiovascular risk from the PREDIMED trial. Forty three percent of them were men (55 to 80 years) and 57% were women (60 to 80 years). All of them were initially free of cardiovascular disease. The recruitment took place in 11 recruiting centers between 2003 and 2009.

Results

After adjusting for age, sex, smoking, diabetes, hypertension, intervention group, family history of coronary heart disease, and leisure-time physical activity, WC and WHtR were found to be directly associated with a higher mortality after 4.8 years median follow-up. The multivariable-adjusted HRs for mortality of WHtR (cut-off points: 0.60, 0.65, 0.70) were 1.02 (0.78–1.34), 1.30 (0.97–1.75) and 1.55 (1.06–2.26). When we used WC (cut-off points: 100, 105 and 110 cm), the multivariable adjusted Hazard Ratios (HRs) for mortality were 1.18 (0.88–1.59), 1.02 (0.74–1.41) and 1.57 (1.19–2.08). In all analyses, BMI exhibited weaker associations with mortality than WC or WHtR. The direct association between WHtR and overall mortality was consistent within each of the three intervention arms of the trial.

Conclusions

Our study adds further support to a stronger association of abdominal obesity than BMI with total mortality among elderly subjects at high risk of cardiovascular disease. We did not find evidence to support that the PREDIMED intervention was able to counterbalance the harmful effects of increased adiposity on total mortality.

Trial Registration

Controlled-Trials.com ISRCTN35739639