Hypertension management in patients with cardiovascular comorbidities.

Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin-angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.

Early sex-dependent differences in metabolic profiles of overweight and adiposity in young children: a cross-sectional analysis.

BACKGROUND: Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. METHODS: Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). RESULTS: In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. CONCLUSIONS: Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.

Validation of Urinary Thiocyanate as a Robust Biomarker of Active Tobacco Smoking in the Prospective Urban and Rural Epidemiological Study.

INTRODUCTION: Tobacco smoking is a leading preventable cause of premature death globally. Urinary thiocyanate is a biomarker of cyanide exposure from tobacco smoke; however, few studies have evaluated its utility in diverse populations of smokers. AIMS AND METHODS: We examined the associations between urinary thiocyanate and self-reported never and current smokers among 1000 participants from 14 countries in the Prospective Urban and Rural Epidemiological study. We analyzed urinary thiocyanate in light and heavy smokers as compared to never-smokers from high- (HICs), middle- (MICs), and low-income countries (LICs) using a validated capillary electrophoresis method in conjunction with standardized questionnaires. RESULTS: The median urinary thiocyanate concentration was 31 µM, which ranged from 8.6 µM to 52 µM for never-smokers (n = 335) and current smokers (n = 660), respectively. Urinary thiocyanate was correlated with daily cigarette consumption (r = 0.621) and total nicotine equivalents (r = 0.514). Thiocyanate also displayed a better dose-response than urinary cotinine. A moderate association of urinary thiocyanate was found in biochemically verified never-smokers (r ~0.38) because of intake of vegetables, fruits, and dairy. Receiver-operating characteristic curves established cutoff values for urinary thiocyanate to differentiate current from never-smokers with an optimal threshold of 23.9 µM (Area Under the Curve or AUC = 0.861), which lowered progressively from HICs, MICs, and LICs. CONCLUSIONS: Elevated thiocyanate was evident in current smokers from high-income countries likely reflecting differences in smoking topography and greater toxicant burden. Background urinary thiocyanate in never-smokers was associated with goitrogenic food intake that obscured detection of secondhand smoke exposure. IMPLICATIONS: Urinary thiocyanate is a sensitive biomarker of active tobacco smoking relative to cotinine that can be measured by an inexpensive capillary electrophoresis assay. Regional cutoff values are demonstrated to improve discrimination of smoking status in developing countries because of differences in smoking habits and cigarette products consumed, as well as intake of goitrogenic foods. Urinary thiocyanate may allow for more reliable estimates of the hazards of tobacco smoking between countries with varying socioeconomic development as compared to self-reports.

Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk.

BACKGROUND: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. METHODS: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. RESULTS: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). CONCLUSIONS: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.uniqueidentifier :NCT00153101.

Normal sex and age-specific parameters in a multi-ethnic population: a cardiovascular magnetic resonance study of the Canadian Alliance for Healthy Hearts and Minds cohort.

BACKGROUND: Despite the growing utility of cardiovascular magnetic resonance (CMR) for cardiac morphology and function, sex and age-specific normal reference values derived from large, multi-ethnic data sets are lacking. Furthermore, most available studies use a simplified tracing methodology. Using a large cohort of participants without history of cardiovascular disease (CVD) or risk factors from the Canadian Alliance for Healthy Heart and Minds, we sought to establish a robust set of reference values for ventricular and atrial parameters using an anatomically correct contouring method, and to determine the influence of age and sex on ventricular parameters. METHODS AND RESULTS: Participants (n = 3206, 65% females; age 55.2 ± 8.4 years for females and 55.1 ± 8.8 years for men) underwent CMR using standard methods for quantitative measurements of cardiac parameters. Normal ventricular and atrial reference values are provided: (1) for males and females, (2) stratified by four age categories, and (3) for different races/ethnicities. Values are reported as absolute, indexed to body surface area, or height. Ventricular volumes and mass were significantly larger for males than females (p < 0.001). Ventricular ejection fraction was significantly diminished in males as compared to females (p < 0.001). Indexed left ventricular (LV) end-systolic, end-diastolic volumes, mass and right ventricular (RV) parameters significantly decreased as age increased for both sexes (p < 0.001). For females, but not men, mean LV and RVEF significantly increased with age (p < 0.001). CONCLUSION: Using anatomically correct contouring methodology, we provide accurate sex and age-specific normal reference values for CMR parameters derived from the largest, multi-ethnic population free of CVD to date. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02220582. Registered 20 August 2014-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02220582 .

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis.

BACKGROUND: Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. METHODS: We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), ß blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). FINDINGS: 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0-5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95-1·04] for ACEIs; 0·96 [0·92-1·01] for ARBs; 0·98 [0·89-1·07] for ß blockers; 1·01 [0·95-1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01-1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93-1·09] for ACEIs; 0·99 [0·92-1·06] for ARBs; 0·99 [0·89-1·11] for ß blockers; 1·04 [0·96-1·13] for calcium channel blockers; 1·00 [0·90-1·10] for thiazides). INTERPRETATION: We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers. FUNDING: British Heart Foundation, National Institute for Health Research, Oxford Martin School.

Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

BACKGROUND: Some studies, mainly from high-income countries (HICs), report that women receive less care (investigations and treatments) for cardiovascular disease than do men and might have a higher risk of death. However, very few studies systematically report risk factors, use of primary or secondary prevention medications, incidence of cardiovascular disease, or death in populations drawn from the community. Given that most cardiovascular disease occurs in low-income and middle-income countries (LMICs), there is a need for comprehensive information comparing treatments and outcomes between women and men in HICs, middle-income countries, and low-income countries from community-based population studies. METHODS: In the Prospective Urban Rural Epidemiological study (PURE), individuals aged 35-70 years from urban and rural communities in 27 countries were considered for inclusion. We recorded information on participants' sociodemographic characteristics, risk factors, medication use, cardiac investigations, and interventions. 168 490 participants who enrolled in the first two of the three phases of PURE were followed up prospectively for incident cardiovascular disease and death. FINDINGS: From Jan 6, 2005 to May 6, 2019, 202 072 individuals were recruited to the study. The mean age of women included in the study was 50·8 (SD 9·9) years compared with 51·7 (10) years for men. Participants were followed up for a median of 9·5 (IQR 8·5-10·9) years. Women had a lower cardiovascular disease risk factor burden using two different risk scores (INTERHEART and Framingham). Primary prevention strategies, such as adoption of several healthy lifestyle behaviours and use of proven medicines, were more frequent in women than men. Incidence of cardiovascular disease (4·1 [95% CI 4·0-4·2] for women vs 6·4 [6·2-6·6] for men per 1000 person-years; adjusted hazard ratio [aHR] 0·75 [95% CI 0·72-0·79]) and all-cause death (4·5 [95% CI 4·4-4·7] for women vs 7·4 [7·2-7·7] for men per 1000 person-years; aHR 0·62 [95% CI 0·60-0·65]) were also lower in women. By contrast, secondary prevention treatments, cardiac investigations, and coronary revascularisation were less frequent in women than men with coronary artery disease in all groups of countries. Despite this, women had lower risk of recurrent cardiovascular disease events (20·0 [95% CI 18·2-21·7] versus 27·7 [95% CI 25·6-29·8] per 1000 person-years in men, adjusted hazard ratio 0·73 [95% CI 0·64-0·83]) and women had lower 30-day mortality after a new cardiovascular disease event compared with men (22% in women versus 28% in men; p<0·0001). Differences between women and men in treatments and outcomes were more marked in LMICs with little differences in HICs in those with or without previous cardiovascular disease. INTERPRETATION: Treatments for cardiovascular disease are more common in women than men in primary prevention, but the reverse is seen in secondary prevention. However, consistently better outcomes are observed in women than in men, both in those with and without previous cardiovascular disease. Improving cardiovascular disease prevention and treatment, especially in LMICs, should be vigorously pursued in both women and men. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study.

BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

BACKGROUND: Global estimates of the effect of common modifiable risk factors on cardiovascular disease and mortality are largely based on data from separate studies, using different methodologies. The Prospective Urban Rural Epidemiology (PURE) study overcomes these limitations by using similar methods to prospectively measure the effect of modifiable risk factors on cardiovascular disease and mortality across 21 countries (spanning five continents) grouped by different economic levels. METHODS: In this multinational, prospective cohort study, we examined associations for 14 potentially modifiable risk factors with mortality and cardiovascular disease in 155 722 participants without a prior history of cardiovascular disease from 21 high-income, middle-income, or low-income countries (HICs, MICs, or LICs). The primary outcomes for this paper were composites of cardiovascular disease events (defined as cardiovascular death, myocardial infarction, stroke, and heart failure) and mortality. We describe the prevalence, hazard ratios (HRs), and population-attributable fractions (PAFs) for cardiovascular disease and mortality associated with a cluster of behavioural factors (ie, tobacco use, alcohol, diet, physical activity, and sodium intake), metabolic factors (ie, lipids, blood pressure, diabetes, obesity), socioeconomic and psychosocial factors (ie, education, symptoms of depression), grip strength, and household and ambient pollution. Associations between risk factors and the outcomes were established using multivariable Cox frailty models and using PAFs for the entire cohort, and also by countries grouped by income level. Associations are presented as HRs and PAFs with 95% CIs. FINDINGS: Between Jan 6, 2005, and Dec 4, 2016, 155 722 participants were enrolled and followed up for measurement of risk factors. 17 249 (11·1%) participants were from HICs, 102 680 (65·9%) were from MICs, and 35 793 (23·0%) from LICs. Approximately 70% of cardiovascular disease cases and deaths in the overall study population were attributed to modifiable risk factors. Metabolic factors were the predominant risk factors for cardiovascular disease (41·2% of the PAF), with hypertension being the largest (22·3% of the PAF). As a cluster, behavioural risk factors contributed most to deaths (26·3% of the PAF), although the single largest risk factor was a low education level (12·5% of the PAF). Ambient air pollution was associated with 13·9% of the PAF for cardiovascular disease, although different statistical methods were used for this analysis. In MICs and LICs, household air pollution, poor diet, low education, and low grip strength had stronger effects on cardiovascular disease or mortality than in HICs. INTERPRETATION: Most cardiovascular disease cases and deaths can be attributed to a small number of common, modifiable risk factors. While some factors have extensive global effects (eg, hypertension and education), others (eg, household air pollution and poor diet) vary by a country's economic level. Health policies should focus on risk factors that have the greatest effects on averting cardiovascular disease and death globally, with additional emphasis on risk factors of greatest importance in specific groups of countries. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Metabolite profiles and the risk of metabolic syndrome in early childhood: a case-control study.

BACKGROUND: Defining the metabolic syndrome (MetS) in children remains challenging. Furthermore, a dichotomous MetS diagnosis can limit the power to study associations. We sought to characterize the serum metabolite signature of the MetS in early childhood using high-throughput metabolomic technologies that allow comprehensive profiling of metabolic status from a biospecimen. METHODS: In the Family Atherosclerosis Monitoring In earLY life (FAMILY) prospective birth cohort study, we selected 228 cases of MetS and 228 matched controls among children age 5 years. In addition, a continuous MetS risk score was calculated for all 456 participants. Comprehensive metabolite profiling was performed on fasting serum samples using multisegment injection-capillary electrophoresis-mass spectrometry. Multivariable regression models were applied to test metabolite associations with MetS adjusting for covariates of screen time, diet quality, physical activity, night sleep, socioeconomic status, age, and sex. RESULTS: Compared to controls, thirteen serum metabolites were identified in MetS cases when using multivariable regression models, and using the quantitative MetS score, an additional eight metabolites were identified. These included metabolites associated with gluconeogenesis (glucose (odds ratio (OR) 1.55 [95% CI 1.25-1.93]) and glutamine/glutamate ratio (OR 0.82 [95% CI 0.67-1.00])) and the alanine-glucose cycle (alanine (OR 1.41 [95% CI 1.16-1.73])), amino acids metabolism (tyrosine (OR 1.33 [95% CI 1.10-1.63]), threonine (OR 1.24 [95% CI 1.02-1.51]), monomethylarginine (OR 1.33 [95% CI 1.09-1.64]) and lysine (OR 1.23 [95% CI 1.01-1.50])), tryptophan metabolism (tryptophan (OR 0.78 [95% CI 0.64-0.95])), and fatty acids metabolism (carnitine (OR 1.24 [95% CI 1.02-1.51])). The quantitative MetS risk score was more powerful than the dichotomous outcome in consistently detecting this metabolite signature. CONCLUSIONS: A distinct metabolite signature of pediatric MetS is detectable in children as young as 5 years old and may improve risk assessment at early stages of development.

Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk analysis from the ONTARGET/TRANSCEND trials.

AIMS: Resting heart rate (RHR) has been shown to be associated with cardiovascular outcomes in various conditions. It is unknown whether different levels of RHR and different associations with cardiovascular outcomes occur in patients with or without diabetes, because the impact of autonomic neuropathy on vascular vulnerability might be stronger in diabetes. METHODS AND RESULTS: We examined 30 937 patients aged 55 years or older with a history of or at high risk for cardiovascular disease and after myocardial infarction, stroke, or with proven peripheral vascular disease from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination followed for a median of 56 months. We analysed the association of mean achieved RHR on-treatment with the primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, the components of the composite primary outcome, and all-cause death as continuous and categorical variables. Data were analysed by Cox regression analysis, ANOVA, and χ2 test. These trials were registered with ClinicalTrials.gov.number NCT00153101. Patients were recruited from 733 centres in 40 countries between 1 December 2001 and 31 July 2008 (ONTARGET) and 1 November 2001 until 30 May 2004 (TRANSCEND). In total, 19 450 patients without diabetes and 11 487 patients with diabetes were stratified by mean RHR. Patients with diabetes compared to no diabetes had higher RHRs (71.8 ± 9.0 vs. 67.9 ± 8.8, P < 0.0001). In the categories of <60 bpm, 60 ≤ 65 bpm, 65 ≤ 70 bpm, 70 ≤ 75 bpm, 75 ≤ 80 bpm and ≥80 bpm, non-diabetic patients had an increased hazard of the primary outcome with mean RHR of 75 ≤ 80 bpm (adjusted hazard ratio [HR] 1.17 (1.01-1.36)) compared to RHR 60 ≤ 65 bpm. For patients with in-trial RHR ≥80 bpm the hazard ratios were highest (diabetes: 1.96 (1.64-2.34), no diabetes: 1.73 (1.49-2.00), For cardiovascular death hazards were also clearly increased at RHR ≥80 bpm (diabetes [1.99, (1.53-2.58)], no diabetes [1.73 (1.38-2.16)]. Similar results were obtained for hospitalization for heart failure and all-cause death while the effect of RHR on myocardial infarction and stroke was less pronounced. Results were robust after adjusting for various risk indicators including beta-blocker use and atrial fibrillation. No significant association to harm was observed at lower RHR. CONCLUSION: Mean RHR above 75-80 b.p.m. was associated with increased risk for cardiovascular outcomes except for stroke. Since in diabetes, high RHR is associated with higher absolute event numbers and patients have higher RHRs, this association might be of particular clinical importance in diabetes. These data suggest that RHR lowering in patients with RHRs above 75-80 b.p.m. needs to be studied in prospective trials to determine if it will reduce outcomes in diabetic and non-diabetic patients at high cardiovascular risk. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.Unique identifier: NCT00153101.

Serum nonesterified fatty acids have utility as dietary biomarkers of fat intake from fish, fish oil, and dairy in women.

Nutritional studies rely on various biological specimens for FA determination, yet it is unclear how levels of serum NEFAs correlate with other circulating lipid pools. Here, we used a high-throughput method (<4 min/sample) based on multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry (MSI-NACE-MS) to investigate whether specific serum NEFAs have utility as biomarkers of dietary fat intake in women. We first identified circulating NEFAs correlated with long-term/habitual food intake among pregnant women with contrasting dietary patterns (n = 50). Acute changes in serum NEFA trajectories were also studied in nonpregnant women (n = 18) following high-dose (5 g/day) fish oil (FO) supplementation or isoenergetic sunflower oil placebo over 56 days. In the cross-sectional study, serum ω-3 FAs correlated with self-reported total ω-3 daily intake, notably EPA as its NEFA (r = 0.46; P = 0.001), whereas pentadecanoic acid was associated with full-fat dairy intake (r = 0.43; P = 0.002), outcomes consistent with results from total FA serum hydrolysates. In the intervention cohort, serum ω-3 NEFAs increased 2.5-fold from baseline within 28 days following FO supplementation, and this increase was most pronounced for EPA (P = 0.0004). Unlike for DHA, circulating EPA as its NEFA also strongly correlated to EPA concentrations measured from erythrocyte phospholipid hydrolysates (r = 0.66; P = 4.6 × 10-10) and was better suited to detect dietary nonadherence. We conclude that MSI-NACE-MS offers a rapid method to quantify serum NEFAs and objectively monitor dietary fat intake in women that is complementary to food-frequency questionnaires.

Cardiovascular outcomes and achieved blood pressure in patients with and without diabetes at high cardiovascular risk.

AIMS: Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk. METHODS AND RESULTS: We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P < 0.0001 for the primary composite outcome, P < 0.01 for all other endpoints). Mean achieved in-trial SBP ≥160 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: adjusted hazard ratio (HR) 2.31 (1.93-2.76)/1.66 (1.36-2.02) compared with non-diabetics with SBP 120 to <140 mmHg], with similar findings for all other endpoints in patients with diabetes, and for MI and stroke in patients without diabetes. In-trial SBP <120 mmHg was associated with increased risk for the combined outcome in patients with diabetes [HR 1.53 (1.27-1.85)], and for cardiovascular death and all-cause death in all patients. In-trial DBP ≥90 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: HR 2.32 (1.91-2.82)/1.61 (1.35-1.93) compared with non-diabetics with DBP 70 to <80 mmHg], with similar findings for all other endpoints, but not for CHF hospitalizations in patients without diabetes. In-trial DBP <70 mmHg was associated with increased risk for the combined outcome in all patients [diabetes/no diabetes: HR 1.77 (1.51-2.06)/1.30 (1.16-1.46)], and also for all other endpoints except stroke. CONCLUSION: High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels (<120 or <70 mmHg) are associated with increased cardiovascular outcomes (except stroke) and death. Patients with diabetes have consistently higher risks over the whole BP range, indicating that achieving optimal BP goals is most impactful in this group. These data favour guidelines taking lower BP boundaries into consideration, in particular in diabetes. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.Unique identifier: NCT00153101.

Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease.

In this second part of a 2-part series on the global burden of cardiovascular disease, we review the proven, effective approaches to the prevention and treatment of cardiovascular disease. We specifically review the management of acute cardiovascular diseases, including acute coronary syndromes and stroke; the care of cardiovascular disease in the ambulatory setting, including medical strategies for vascular disease, atrial fibrillation, and heart failure; surgical strategies for arterial revascularization, rheumatic and other valvular heart disease, and symptomatic bradyarrhythmia; and approaches to the prevention of cardiovascular disease, including lifestyle factors, blood pressure control, cholesterol-lowering, antithrombotic therapy, and fixed-dose combination therapy. We also discuss cardiovascular disease prevention in diabetes mellitus; digital health interventions; the importance of socioeconomic status and universal health coverage. We review building capacity for conduction cardiovascular intervention through strengthening healthcare systems, priority setting, and the role of cost effectiveness.

Achieved diastolic blood pressure and pulse pressure at target systolic blood pressure (120-140 mmHg) and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.

Aims: Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk. Methods: We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable. Results: In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15-1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26-1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47-2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04-1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP. Conclusion: Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.

Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.

BACKGROUND: Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes. METHODS: In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2. These trials were registered with ClinicalTrials.gov, number NCT00153101. FINDINGS: Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. INTERPRETATION: Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. FUNDING: Boehringer Ingelheim.

Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study.

BACKGROUND: The relationship between macronutrients and cardiovascular disease and mortality is controversial. Most available data are from European and North American populations where nutrition excess is more likely, so their applicability to other populations is unclear. METHODS: The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35-70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3-9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering. FINDINGS: During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs lowest quintile [quintile 1] category, HR 1·28 [95% CI 1·12-1·46], ptrend=0·0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 [95% CI 0·67-0·87], ptrend<0·0001; saturated fat, HR 0·86 [0·76-0·99], ptrend=0·0088; monounsaturated fat: HR 0·81 [0·71-0·92], ptrend<0·0001; and polyunsaturated fat: HR 0·80 [0·71-0·89], ptrend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 [95% CI 0·64-0·98], ptrend=0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. INTERPRETATION: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).

Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease.

BACKGROUND: Percutaneous coronary intervention (PCI) relieves angina in patients with stable ischemic heart disease, but clinical trials have not shown that it improves survival. Between June 1999 and January 2004, we randomly assigned 2287 patients with stable ischemic heart disease to an initial management strategy of optimal medical therapy alone (medical-therapy group) or optimal medical therapy plus PCI (PCI group) and did not find a significant difference in the rate of survival during a median follow-up of 4.6 years. We now report the rate of survival among the patients who were followed for up to 15 years. METHODS: We obtained permission from the patients at the Department of Veterans Affairs (VA) sites and some non-VA sites in the United States to use their Social Security numbers to track their survival after the original trial period ended. We searched the VA national Corporate Data Warehouse and the National Death Index for survival information and the dates of death from any cause. We calculated survival according to the Kaplan-Meier method and used a Cox proportional-hazards model to adjust for significant between-group differences in baseline characteristics. RESULTS: Extended survival information was available for 1211 patients (53% of the original population). The median duration of follow-up for all patients was 6.2 years (range, 0 to 15); the median duration of follow-up for patients at the sites that permitted survival tracking was 11.9 years (range, 0 to 15). A total of 561 deaths (180 during the follow-up period in the original trial and 381 during the extended follow-up period) occurred: 284 deaths (25%) in the PCI group and 277 (24%) in the medical-therapy group (adjusted hazard ratio, 1.03; 95% confidence interval, 0.83 to 1.21; P=0.76). CONCLUSIONS: During an extended-follow-up of up to 15 years, we did not find a difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease. (Funded by the VA Cooperative Studies Program and others; COURAGE ClinicalTrials.gov number, NCT00007657.).

Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study.

BACKGROUND: Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents. METHODS: We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35-70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11,963). FINDINGS: We included 114,970 adults, of whom 12,904 (11%) were from high-income countries (HICs), 24,408 (21%) were from upper-middle-income countries (UMICs), 48,845 (43%) were from lower-middle-income countries (LMICs), and 28,813 (25%) were from low-income countries (LICs). Median follow-up was 4.3 years (IQR 3.0-6.0). Current drinking was reported by 36,030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0.76 [95% CI 0.63-0.93]), but increased alcohol-related cancers (HR 1.51 [1.22-1.89]) and injury (HR 1.29 [1.04-1.61]). High intake was associated with increased mortality (HR 1.31 [1.04-1.66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0.84 [0.77-0.92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1.07 [0.95-1.21]; pinteraction<0.0001). INTERPRETATION: Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use. 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.