Angiotensin-converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin–angiotensin hormonal cascade. We assessed whether plasma ACE2 concentrations were associated with greater risk ...of death or cardiovascular disease events.
We used data from the Prospective Urban Rural Epidemiology (PURE) prospective study to conduct a case-cohort analysis within a subset of PURE participants (from 14 countries across five continents: Africa, Asia, Europe, North America, and South America). We measured plasma concentrations of ACE2 and assessed potential determinants of plasma ACE2 levels as well as the association of ACE2 with cardiovascular events.
We included 10 753 PURE participants in our study. Increased concentration of plasma ACE2 was associated with increased risk of total deaths (hazard ratio HR 1·35 per 1 SD increase 95% CI 1·29–1·43) with similar increases in cardiovascular and non-cardiovascular deaths. Plasma ACE2 concentration was also associated with higher risk of incident heart failure (HR 1·27 per 1 SD increase 1·10–1·46), myocardial infarction (HR 1·23 per 1 SD increase 1·13–1·33), stroke (HR 1·21 per 1 SD increase 1·10–1·32) and diabetes (HR 1·44 per 1 SD increase 1·36–1·52). These findings were independent of age, sex, ancestry, and traditional cardiac risk factors. With the exception of incident heart failure events, the independent relationship of ACE2 with the clinical endpoints, including death, remained robust after adjustment for BNP. The highest-ranked determinants of ACE2 concentrations were sex, geographic ancestry, and body-mass index (BMI). When compared with clinical risk factors (smoking, diabetes, blood pressure, lipids, and BMI), ACE2 was the highest ranked predictor of death, and superseded several risk factors as a predictor of heart failure, stroke, and myocardial infarction.
Increased plasma ACE2 concentration was associated with increased risk of major cardiovascular events in a global study.
Canadian Institute of Health Research, Heart & Stroke Foundation of Canada, and Bayer.
Summary Background Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors ...for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. Methods We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. Findings Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases 10 388 with ischaemic stroke and 3059 intracerebral haemorrhage and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72–3·28; PAR 47·9%, 99% CI 45·1–50·6), regular physical activity (0·60, 0·52–0·70; 35·8%, 27·7–44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65–2·06 for highest vs lowest tertile; 26·8%, 22·2–31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53–0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index mAHEI; 23·2%, 18·2–28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27–1·64 for highest vs lowest tertile; 18·6%, 13·3–25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78–2·72; 17·4%, 13·1–22·6), current smoking (1·67, 1·49–1·87; 12·4%, 10·2–14·9), cardiac causes (3·17, 2·68–3·75; 9·1%, 8·0–10·2), alcohol consumption (2·09, 1·64–2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4–9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05–1·30; 3·9%, 1·9–7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). Interpretation Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.
Most data regarding the association between the glycemic index and cardiovascular disease come from high-income Western populations, with little information from non-Western countries with low or ...middle incomes. To fill this gap, data are needed from a large, geographically diverse population.
This analysis includes 137,851 participants between the ages of 35 and 70 years living on five continents, with a median follow-up of 9.5 years. We used country-specific food-frequency questionnaires to determine dietary intake and estimated the glycemic index and glycemic load on the basis of the consumption of seven categories of carbohydrate foods. We calculated hazard ratios using multivariable Cox frailty models. The primary outcome was a composite of a major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, stroke, and heart failure) or death from any cause.
In the study population, 8780 deaths and 8252 major cardiovascular events occurred during the follow-up period. After performing extensive adjustments comparing the lowest and highest glycemic-index quintiles, we found that a diet with a high glycemic index was associated with an increased risk of a major cardiovascular event or death, both among participants with preexisting cardiovascular disease (hazard ratio, 1.51; 95% confidence interval CI, 1.25 to 1.82) and among those without such disease (hazard ratio, 1.21; 95% CI, 1.11 to 1.34). Among the components of the primary outcome, a high glycemic index was also associated with an increased risk of death from cardiovascular causes. The results with respect to glycemic load were similar to the findings regarding the glycemic index among the participants with cardiovascular disease at baseline, but the association was not significant among those without preexisting cardiovascular disease.
In this study, a diet with a high glycemic index was associated with an increased risk of cardiovascular disease and death. (Funded by the Population Health Research Institute and others.).
Summary Background Reduced muscular strength, as measured by grip strength, has been associated with an increased risk of all-cause and cardiovascular mortality. Grip strength is appealing as a ...simple, quick, and inexpensive means of stratifying an individual's risk of cardiovascular death. However, the prognostic value of grip strength with respect to the number and range of populations and confounders is unknown. The aim of this study was to assess the independent prognostic importance of grip strength measurement in socioculturally and economically diverse countries. Methods The Prospective Urban-Rural Epidemiology (PURE) study is a large, longitudinal population study done in 17 countries of varying incomes and sociocultural settings. We enrolled an unbiased sample of households, which were eligible if at least one household member was aged 35–70 years and if household members intended to stay at that address for another 4 years. Participants were assessed for grip strength, measured using a Jamar dynamometer. During a median follow-up of 4·0 years (IQR 2·9–5·1), we assessed all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, myocardial infarction, stroke, diabetes, cancer, pneumonia, hospital admission for pneumonia or chronic obstructive pulmonary disease (COPD), hospital admission for any respiratory disease (including COPD, asthma, tuberculosis, and pneumonia), injury due to fall, and fracture. Study outcomes were adjudicated using source documents by a local investigator, and a subset were adjudicated centrally. Findings Between January, 2003, and December, 2009, a total of 142 861 participants were enrolled in the PURE study, of whom 139 691 with known vital status were included in the analysis. During a median follow-up of 4·0 years (IQR 2·9–5·1), 3379 (2%) of 139 691 participants died. After adjustment, the association between grip strength and each outcome, with the exceptions of cancer and hospital admission due to respiratory illness, was similar across country-income strata. Grip strength was inversely associated with all-cause mortality (hazard ratio per 5 kg reduction in grip strength 1·16, 95% CI 1·13–1·20; p<0·0001), cardiovascular mortality (1·17, 1·11–1·24; p<0·0001), non-cardiovascular mortality (1·17, 1·12–1·21; p<0·0001), myocardial infarction (1·07, 1·02–1·11; p=0·002), and stroke (1·09, 1·05–1·15; p<0·0001). Grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure. We found no significant association between grip strength and incident diabetes, risk of hospital admission for pneumonia or COPD, injury from fall, or fracture. In high-income countries, the risk of cancer and grip strength were positively associated (0·916, 0·880–0·953; p<0·0001), but this association was not found in middle-income and low-income countries. Interpretation This study suggests that measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease. Further research is needed to identify determinants of muscular strength and to test whether improvement in strength reduces mortality and cardiovascular disease. Funding Full funding sources listed at end of paper (see Acknowledgments).
The optimal range of sodium intake for cardiovascular health is controversial.
We obtained morning fasting urine samples from 101,945 persons in 17 countries and estimated 24-hour sodium and ...potassium excretion (used as a surrogate for intake). We examined the association between estimated urinary sodium and potassium excretion and the composite outcome of death and major cardiovascular events.
The mean estimated sodium and potassium excretion was 4.93 g per day and 2.12 g per day, respectively. With a mean follow-up of 3.7 years, the composite outcome occurred in 3317 participants (3.3%). As compared with an estimated sodium excretion of 4.00 to 5.99 g per day (reference range), a higher estimated sodium excretion (≥ 7.00 g per day) was associated with an increased risk of the composite outcome (odds ratio, 1.15; 95% confidence interval CI, 1.02 to 1.30), as well as increased risks of death and major cardiovascular events considered separately. The association between a high estimated sodium excretion and the composite outcome was strongest among participants with hypertension (P=0.02 for interaction), with an increased risk at an estimated sodium excretion of 6.00 g or more per day. As compared with the reference range, an estimated sodium excretion that was below 3.00 g per day was also associated with an increased risk of the composite outcome (odds ratio, 1.27; 95% CI, 1.12 to 1.44). As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a reduced risk of the composite outcome.
In this study in which sodium intake was estimated on the basis of measured urinary excretion, an estimated sodium intake between 3 g per day and 6 g per day was associated with a lower risk of death and cardiovascular events than was either a higher or lower estimated level of intake. As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a lower risk of death and cardiovascular events. (Funded by the Population Health Research Institute and others.).
Cardiovascular disease (CVD) is the major cause of death in Saudi Arabia. We aimed to assess associated demographic, behavioral, and CVD risk factors as part of the Prospective Urban Rural ...Epidemiology (PURE) study.
PURE is a global cohort study of adults ages 35-70 years in 20 countries. PURE-Saudi study participants were recruited from 19 urban and 6 rural communities randomly selected from the Central province (Riyadh and Alkharj) between February 2012 and January 2015. Data were stratified by age, sex, and urban vs rural and summarized as means and standard deviations for continuous variables and as numbers and percentages for categorical variables. Proportions and means were compared between men and women, among age groups, and between urban and rural areas, using Chi-square test and t-tests, respectively.
The PURE-Saudi study enrolled 2047 participants (mean age, 46.5 ± 9.12 years; 43.1% women; 24.5% rural). Overall, 69.4% had low physical activity, 49.6% obesity, 34.4% unhealthy diet, 32.1% dyslipidemia, 30.3% hypertension, and 25.1% diabetes. In addition, 12.2% were current smokers, 15.4% self-reported feeling sad, 16.9% had a history of periods of stress, 6.8% had permanent stress, 1% had a history of stroke, 0.6% had heart failure, and 2.5% had coronary heart disease (CHD). Compared to women, men were more likely to be current smokers and have diabetes and a history of CHD. Women were more likely to be obese, have central obesity, self-report sadness, experience stress, feel permanent stress, and have low education. Compared to participants in urban areas, those in rural areas had higher rates of diabetes, obesity, and hypertension, and lower rates of unhealthy diet, self-reported sadness, stress (several periods), and permanent stress. Compared to middle-aged and older individuals, younger participants more commonly reported an unhealthy diet, permanent stress, and feeling sad.
These results of the PURE-Saudi study revealed a high prevalence of unhealthy lifestyle and CVD risk factors in the adult Saudi population, with higher rates in rural vs urban areas. National public awareness programs and multi-faceted healthcare policy changes are urgently needed to reduce the future burden of CVD risk and mortality.
Summary Background Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those ...individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. Methods In this pooled analysis, we studied 133 118 individuals (63 559 with hypertension and 69 559 without hypertension), median age of 55 years (IQR 45–63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4·2 years (IQR 3·0–5·0) and blood pressure. Findings Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2·08 mm Hg change per g sodium increase) compared with individuals without hypertension (1·22 mm Hg change per g; pinteraction <0·0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 11% of population with hypertension: hazard ratio HR 1·23 95% CI 1·11–1·37; p<0·0001) and less than 3 g/day (7006 11% of population with hypertension: 1·34 1·23–1·47; p<0·0001) were both associated with increased risk compared with sodium excretion of 4–5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4–5 g/day (18 508 27% of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥7 g/day in 6271 9% of the population without hypertension; HR 0·90 95% CI 0·76–1·08; p=0·2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 11% of the population without hypertension; HR 1·26 95% CI 1·10–1·45; p=0·0009). Interpretation Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets. Funding Full funding sources listed at end of paper (see Acknowledgments).
More than 80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-income countries, but the reasons are unknown.
We enrolled 156,424 persons from 628 urban and rural ...communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) and assessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years.
The mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P=0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001).
Although the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in high-income countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.).
Higher levels of sodium intake are reported to be associated with higher blood pressure. Whether this relationship varies according to levels of sodium or potassium intake and in different ...populations is unknown.
We studied 102,216 adults from 18 countries. Estimates of 24-hour sodium and potassium excretion were made from a single fasting morning urine specimen and were used as surrogates for intake. We assessed the relationship between electrolyte excretion and blood pressure, as measured with an automated device.
Regression analyses showed increments of 2.11 mm Hg in systolic blood pressure and 0.78 mm Hg in diastolic blood pressure for each 1-g increment in estimated sodium excretion. The slope of this association was steeper with higher sodium intake (an increment of 2.58 mm Hg in systolic blood pressure per gram for sodium excretion >5 g per day, 1.74 mm Hg per gram for 3 to 5 g per day, and 0.74 mm Hg per gram for <3 g per day; P<0.001 for interaction). The slope of association was steeper for persons with hypertension (2.49 mm Hg per gram) than for those without hypertension (1.30 mm Hg per gram, P<0.001 for interaction) and was steeper with increased age (2.97 mm Hg per gram at >55 years of age, 2.43 mm Hg per gram at 45 to 55 years of age, and 1.96 mm Hg per gram at <45 years of age; P<0.001 for interaction). Potassium excretion was inversely associated with systolic blood pressure, with a steeper slope of association for persons with hypertension than for those without it (P<0.001) and a steeper slope with increased age (P<0.001).
In this study, the association of estimated intake of sodium and potassium, as determined from measurements of excretion of these cations, with blood pressure was nonlinear and was most pronounced in persons consuming high-sodium diets, persons with hypertension, and older persons. (Funded by the Heart and Stroke Foundation of Ontario and others.).
Summary Background WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously ...reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. Methods We analysed information about availability and costs of cardiovascular disease medicines (aspirin, β blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. Findings Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24 776), 33% of lower middle-income countries (13 253 of 40 023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16 874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio OR 0·16, 95% CI 0·04–0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04–0·55). Interpretation Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. Funding Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.
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