ObjectiveTo examine the dose-response associations between accelerometer assessed total physical activity, different intensities of physical activity, and sedentary time and all cause mortality.DesignSystematic review and harmonised meta-analysis.Data sourcesPubMed, PsycINFO, Embase, Web of Science, Sport Discus from inception to 31 July 2018.Eligibility criteriaProspective cohort studies assessing physical activity and sedentary time by accelerometry and associations with all cause mortality and reported effect estimates as hazard ratios, odds ratios, or relative risks with 95% confidence intervals.Data extraction and analysisGuidelines for meta-analyses and systematic reviews for observational studies and PRISMA guidelines were followed. Two authors independently screened the titles and abstracts. One author performed a full text review and another extracted the data. Two authors independently assessed the risk of bias. Individual level participant data were harmonised and analysed at study level. Data on physical activity were categorised by quarters at study level, and study specific associations with all cause mortality were analysed using Cox proportional hazards regression analyses. Study specific results were summarised using random effects meta-analysis.Main outcome measureAll cause mortality.Results39 studies were retrieved for full text review; 10 were eligible for inclusion, three were excluded owing to harmonisation challenges (eg, wrist placement of the accelerometer), and one study did not participate. Two additional studies with unpublished mortality data were also included. Thus, individual level data from eight studies (n=36 383; mean age 62.6 years; 72.8% women), with median follow-up of 5.8 years (range 3.0-14.5 years) and 2149 (5.9%) deaths were analysed. Any physical activity, regardless of intensity, was associated with lower risk of mortality, with a non-linear dose-response. Hazards ratios for mortality were 1.00 (referent) in the first quarter (least active), 0.48 (95% confidence interval 0.43 to 0.54) in the second quarter, 0.34 (0.26 to 0.45) in the third quarter, and 0.27 (0.23 to 0.32) in the fourth quarter (most active). Corresponding hazards ratios for light physical activity were 1.00, 0.60 (0.54 to 0.68), 0.44 (0.38 to 0.51), and 0.38 (0.28 to 0.51), and for moderate-to-vigorous physical activity were 1.00, 0.64 (0.55 to 0.74), 0.55 (0.40 to 0.74), and 0.52 (0.43 to 0.61). For sedentary time, hazards ratios were 1.00 (referent; least sedentary), 1.28 (1.09 to 1.51), 1.71 (1.36 to 2.15), and 2.63 (1.94 to 3.56).ConclusionHigher levels of total physical activity, at any intensity, and less time spent sedentary, are associated with substantially reduced risk for premature mortality, with evidence of a non-linear dose-response pattern in middle aged and older adults.Systematic review registrationPROSPERO CRD42018091808.

Summary Background Comprehensive long-term data on atrial fibrillation trends in men and women are scant. Methods We investigated trends in atrial fibrillation incidence, prevalence, and risk factors, and in stroke and mortality following its onset in Framingham Heart Study participants (n=9511) from 1958 to 2007. To accommodate sex differences in atrial fibrillation risk factors and disease manifestations, sex-stratified analyses were performed. Findings During 50 years of observation (202,417 person-years), there were 1,544 new-onset atrial fibrillation cases (46.8% women). We observed about a fourfold increase in the age-adjusted prevalence and more than a tripling in age-adjusted incidence of atrial fibrillation (prevalence 20.4 versus 96.2 per 1000 person-years in men; 13.7 versus 49.4 in women; incidence rates in first versus last decade 3.7 versus 13.4 per 1000 person-years in men; 2.5 versus 8.6 in women, ptrend<0.0001). For atrial fibrillation diagnosed by ECG during routine Framingham examinations, age-adjusted prevalence increased (12.6versus 25.7 per 1000 person-years in men; 8.1 versus 11.8 in women, ptrend<0.0001). The age-adjusted incidence increased, but did not achieve statistical significance. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 73.5% decline in stroke and a 25.4% decline in mortality following atrial fibrillation onset (ptrend=0.0001, ptrend=0.003, respectively). Interpretation Our data suggest that observed trends of increased incidence of atrial fibrillation in the community were partially due to enhanced surveillance. Stroke occurrence and mortality following atrial fibrillation onset declined over the decades, and prevalence increased approximately fourfold. The hazards for atrial fibrillation risk factors remained fairly constant. Our data indicate a need for measures to enhance early detection of atrial fibrillation through increased awareness coupled with targeted screening programs, and risk factor-specific prevention.

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We thank Dr O'Rourke et al, Drs Safar and Jankowski, and Dr Weber et al for their interest in our recent article. 1 Dr O'Rourke et al comment that the "comprehensive battery of measures of aortic stiffness and wave reflection" described in previous communications on this cohort were not mentioned. We reported results for all relevant tonometry data available from the Framingham Heart Study offspring and original cohorts at the noted examination cycles. Although we have assessed additional hemodynamic measures during subsequent examinations in the Framingham offspring and third-generation cohorts, because of insufficient follow-up, we have not yet assessed relations with outcomes for those measures. Dr O'Rourke et al suggest that we dismissed multiple studies that showed wave reflection to be important in predicting outcome. There have been several studies in highly selected patient groups that have shown a relation between augmentation index (AI) and prevalent or incident cardiovascular disease. However, as summarized in a recent editorial, 2 even in patients with prevalent cardiovascular disease, the preponderance of evidence suggests no independent association between AI and events in a model that includes standard risk factors. Dr O'Rourke et al note that we made no mention of a previous study from Framingham that evaluated dicrotic notch position as a measure of arterial stiffness. 3 Kannel et al 3 detailed the considerable limitations of dicrotic notch position as a measure of arterial stiffness or wave reflection and found no relation between dicrotic notch location and incident stroke in a model that included systolic blood pressure.Dr O'Rourke et al speculate that the brachial artery wall cannot be applanated (flattened) against bone during tonometry. To minimize this potential limitation, we trained operators to stay proximal and medial to the aponeurosis, while pinning the brachial artery against the substantial bony backing provided by the distal humerus. Analyses were performed by trained reviewers blinded to clinical characteristics. Dr O'Rourke et al indicate that in other studies, mean values of pressure amplification and AI were higher than those we reported. The studies cited by Dr O'Rourke used the SphygmoCor transfer function, which overestimates aortic-brachial amplification. 4 Drs Safar and Jankowski and Dr Weber et al note that pulse pressure (PP) is a better predictor of atherosclerotic than heart failure events. They requested results for AI, central PP, and PP amplification after excluding 57 heart failure events. To respond, we ran the requested models excluding heart failure events and did not find significant relations with outcome (PϾ0.7 for all). They further note that presentation of hazard ratios for peripheral blood pressure would allow better assessment of the predictive value of central versus peripheral blood pressure. In the base risk factor model without tonometry variables, peripheral systolic pressure was associated with a hazard ratio of 1.23 (95% confidence interval, 1...

peripheral arterial disease (PAD) in people with diabetes; (2) the biology of PAD in people with diabetes; (3) how PAD is best diagnosed in people with diabetes; and (4) appropriate treatments for PAD in people with diabetes. Some interesting conclusions of the consensus conference are as follows:Vascular abnormalities in people with diabetes increase with duration of diabetes and worsening blood pressure control. People with diabetes are more prone to sudden ischemic events secondary to arterial thrombosis of underlying atherosclerotic lesions. Abnormalities in blood rheology in people with diabetes are associated with elevations in blood viscosity and fibrinogen. Both blood viscosity and fibrinogen abnormalities have been associated with the presence, development, and complications of PAD. Using the ankle-brachial index (ABI), the prevalence of PAD in people with diabetes Ͼ40 years of age is 20% and is as high as 29% in those Ͼ50 years of age. All people with diabetes Ͼ50 years of age should have a screening ABI. A screening ABI should also be considered in people with diabetes who are Ͻ50 years of age and who have other PAD risk factors such as smoking, hypertension, hyperlipidemia, or a duration of diabetes greater than 10 years.Comment: This consensus statement comes from a panel of highly respected experts. Its recommendations are likely to have an impact on clinical care. In particular, the recommendation for screening ABIs may have immediate impact on vascular laboratories. Those who manage vascular laboratories are placed in a difficult position. The panel recommends screening ABIs, but screening studies are generally not reimbursed.

Summary The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator-1 α (PGC-1α) regulates metabolic genes in skeletal muscle, and contributes substantially to the response of muscle to exercise. Muscle specific PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolic profiling approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a novel small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipose tissue and fatty acid β-oxidation in hepatocytes both in vitro and in vivo through a PPARα mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

Riassunto. L'ipertensione arteriosa rappresenta il principale fattore di rischio per lo sviluppo di malattie cardiovascolari e renali. Numerose e solide evidenze sono disponibili a sostegno dei beneficî derivanti dalla riduzione dei valori pressori in termini di riduzione del rischio di sviluppare infarto del miocardio, ictus cerebrale e morte per cause cardiovascolari. È importante sottolineare, tuttavia, come i pazienti affetti da ipertensione arteriosa abbiano anche un rischio aumentato di sviluppare insufficienza cardiaca, indipendentemente dalla presenza di ipertrofia o disfunzione ventricolare sinistra. È stato, inoltre, dimostrato come il controllo dei valori pressori determini una significativa riduzione del rischio di sviluppare questa complicanza. In particolare, studi di meta-analisi condotti nel corso degli ultimi anni hanno consentito di dimostrare come l'impiego di diuretici o di farmaci in grado di antagonizzare il sistema renina-angiotensina sia maggiormente efficace in termini di prevenzione dello sviluppo di insufficienza cardiaca rispetto a strategie basate su calcio-antagonisti e beta-bloccanti.Nel presente articolo verranno discussi ed analizzati i principali aspetti fisiopatologici coinvolti nella progressione dall'ipertensione arteriosa allo scompenso cardiaco e le possibili strategie terapeutiche in grado di ridurre o prevenire tale progressione.Parole chiave. Ipertensione arteriosa, prevenzione cardiovascolare, scompenso cardiaco, terapia antiipertensiva.The progression from hypertension to congestive heart failure. Summary.Arterial hypertension still represents one of the major modifiable risk factors for cardiovascular and renal disease. Solid evidences are available demonstrating the large and significant benefits deriving from blood pressure lowering therapies in terms of reduced incidence of major cardiovascular events, including myocardial infarction, ischemic stroke and cardiovascular death. It should be also noted, however, that hypertensive patients are at increased risk of developing congestive heart failure, being this risk substantially independent by the concomitant presence of left ventricular hypertrophy or dysfunction. Indeed, it has been demonstrated that blood pressure reduction and control significantly reduce the risk of developing congestive heart failure. In particular, several recent meta-analyses have demonstrated that the use of diuretics and renin-angiotensin system blockers is superior to calcium-antagonists and betablockers in terms of prevention of new-onset heart failure.The present paper overviews the main pathophysiological aspects of the progression from arterial hypertension to congestive heart failure and the potential therapeutic interventions able to reduce or prevent this progression.