Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Comparing ultrasonographically assessed carotid and abdominal aorta plaques in cardiovascular disease risk estimation.

BACKGROUND: Individual risk estimation is an essential part of cardiovascular (CV) disease prevention. Several imaging parameters have been studied for this purpose. Based on mounting evidence, international guidelines recommend the ultrasound assessment of carotid artery plaques to refine individual risk estimation. Previous studies have not compared carotid artery and abdominal aorta plaques in CV risk estimation. Our aim was to explore this matter in a prospective study setting. METHODS: Participants were part of the Oulu Project Elucidating Risk of Atherosclerosis (OPERA) project. All participants (n = 1007, 50% males, aged 51.3 ± 6.0 years) were clinically examined in the beginning of 1990's and followed until the end 2014 for fatal and non-fatal CV events. RESULTS: During a median follow-up of 22.5 (17.5-23.2) years, 246 (24%) participants suffered a CV event and 79 (32%) of those CV events were fatal. When compared to those without plaques, both carotid (hazard ratio, HR 2.854 [95% confidence interval, CI, 2.188-3.721, p < 0.001) and abdominal aorta plaques (HR 2.534 [1.503-4.274], p < 0.001) were major risk factors for CV events as an aggregate endpoint. These associations remained even after adjusting the multivariable models with age, sex, systolic blood pressure, smoking, diabetes, LDL cholesterol, and with previous CV events (coronary artery disease and stroke/transient ischemic attack). However, only carotid plaques were significant risk factors for fatal CV events: multivariable adjusted HR 2.563 (1.452-4.524), p = 0.001. Furthermore, reclassification and discrimination parameters were improved only when carotid plaques were added to a baseline risk model. Adding abdominal aorta plaques to the baseline risk model improved C-statistic from 0.718 (0.684-0.751) to 0.721 (0.688-0.754) whereas carotid plaques improved it to 0.743 (0.710-0.776). CONCLUSIONS: Both carotid and abdominal aorta plaques are significant risk factors for CV events, but only carotid plaques provide prognostic information beyond traditional CV risk factors on fatal CV events. If one ultrasound parameter for plaque detection and CV risk estimation had to be chosen, carotid plaques may be preferred over abdominal aorta.

Nonalcoholic fatty liver disease and its prognosis associates with shorter leucocyte telomeres in a 21-year follow-up study.

Leucocyte telomere length (LTL) has been associated with nonalcoholic fatty liver disease (NAFLD), but the evidence is imperfect. Furthermore, liver fibrosis has been shown to correlate with mortality and recent studies have also found associations with LTL and fibrosis suggesting that LTL may have additional prognostic value in liver diseases. Our objective was to study the association of LTL and NAFLD and evaluate the association of LTL in prognosis of NAFLD subjects. Study subjects (n = 847) were middle-aged hypertensive patients. All participants were evaluated for NAFLD and their LTL was measured at baseline. Outcomes were obtained from Finnish Causes-of-Death Register and the Care Register for Health Care in Statistics Finland to the end of 2014. An inverse association with NAFLD prevalence and LTL length was observed (p < .001 for trend). Shortest telomere tertile possessed statistically significantly more NAFLD subjects even with multivariate analysis (shortest vs. middle tertile HR 1.98 p = .006 and shortest vs. longest tertile HR 2.03 p = .007). For the study period, mortality of the study group showed statistically significant relation with telomere length in univariate but not for multivariate analysis. In subgroup analysis, LTL did not associate with prognosis of non-NAFLD subjects. However, LTL was inversely associated with overall mortality in the subjects with NAFLD in both univariate (HR 0.16 p = .007) and multivariate analysis (HR 0.20 p = .045). In middle-aged Caucasian cohort, shorter leucocyte telomeres associated independently with increased prevalence of NAFLD. Shorter LTL was not associated with mortality in non-NAFLD patients whereas it predicted mortality of NAFLD patients independently.

Soluble ST2, a biomarker of fibrosis, is associated with multiple risk factors, chronic diseases and total mortality in the OPERA study.

Several diseases have a deleterious fibrosis component. Biomarkers indicating potential clinical utility that reliably reflect the degree of fibrosis have been introduced, one of them being soluble suppression of tumorigenicity 2 (sST2). The aim of our study was to explore the association of cardiometabolic risk factors, different diseases and total mortality with biomarker sST2 and see, how fibrosis is portrayed in these conditions. In addition, we were interested to see if sST2 levels could predict fibrosis in the long-term (21 years). The Oulu Project Elucidating Risk of Atherosclerosis (OPERA) survey collected data on the same individuals in years 1991-1993 (baseline, n = 1045), 2013-2014 (follow-up, n = 600) and mortality data until year 2019. Smoking at baseline retained a significant association with sST2 levels reflecting fibrosis development 20 years later. In the multivariate model male gender, diabetes, quick-index, levels of alanine aminotransferase (ALAT), high-density lipoprotein (HDL) cholesterol and high-sensitivity C-reactive protein (hsCRP) were associated with elevated sST2 levels at the examination 2013-2014. sST2 levels were higher among subjects suffering from cardiovascular disease (p = .031), cancer (p = .021), mild cognitive decline (p = .046) and diabetes (p < .001). Total mortality was assessed by using the Cox proportional hazard survival model analysis. sST2 (log-transformed) was an independent predictor of total mortality (HR 9.4; 95% CI 2.8-31.4, p<.001) when age, gender, diabetes, smoking, quick-index, levels of ALAT, HDL-cholesterol and hsCRP were added as covariates. In addition, elevated levels indicated worse prognosis and predicted mortality.

The validity of hospital discharge register data on non-ST-elevation and ST-elevation myocardial infarction in Finland.

Objectives. To examine the validity of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) diagnoses in Finnish nation-wide hospital discharge register (HDR). Design. In the first stage of the study, we sampled 180 patients treated in 1996-2012 for MI in three different hospitals, Oulu university hospital, Turku university hospital and North Karelia Central hospital, 60 patients in each hospital. A cardiology resident classified the patients on the basis of ECG finding into following categories: NSTEMI, STEMI or not classifiable myocardial infarction (NCMI). In the second stage of the study, we sampled altogether 270 additional patients i.e. 90 patients per hospital. Patients were treated between 2012-2014 for STEMI (n = 3 × 30), NSTEMI (n = 3 × 30), and NCMI (n = 3 × 30). The ECGs of these patients were independently evaluated by the cardiology resident and a senior cardiologist and compared with the HDR diagnosis. Results. In the first stage of the study, the agreement between the ECG coding of the cardiology resident and the HDR diagnoses was poor (Cohen's kappa coefficient 0.38 (95% CI 0.10-0.32). In the second stage, the agreement remained at the same poor level (Cohen's kappa = 0.22 (95% CI 0.11-0.03)). The agreement between the cardiology resident and the senior cardiologist was, however, good (Cohen's kappa = 0.75 (95% CI 0.65-0.85)). Conclusions. Our results show that the division of MI diagnoses to STEMI and NSTEMI is not reliable in the Finnish HDR. These diagnoses should not be used as outcomes in scientific research without additional verification from the original ECGs.

Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study).

Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011-4.173, p = .046)]. However, PNPLA3 rs738409 [1.049 (0.650-1.692, p = .844)], TM6SF2 rs58542926 [0.721 (0.369-1.411, p = .340)] or MBOAT7 rs641738 [0.885 (0.543-1.439, p = .621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p = .013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.

Non-dipping blood pressure pattern and new-onset diabetes in a 21-year follow-up.

Purpose: Non-dipping blood pressure (BP) pattern has been associated with metabolic changes and cardiovascular events. With regard of diabetes, studies are scarce. Our aim was to investigate if there is an association between changes in dipping patterns and incidence of diabetes. Materials and methods: A 24-h ambulatory BP measurement was recorded in addition to other laboratory measurements, and a questionnaire and physical examination were carried out in the baseline study and after 21-year follow-up among a study population (n = 449) consisting of randomly selected middle-aged Finnish females and males without diabetes. Results: 128 (28.5%) developed diabetes during the follow-up. The incidence of new-onset diabetes was the highest, 41.0%, among those subjects who were non-dippers (their systolic BP declined <10% from daytime to nighttime) in the baseline and also in the follow-up study, while the incidence of diabetes was 19.6% in the dipper - dipper (a nighttime decline of systolic BP 10% or more) group (p = 0.003). The difference remained statistically significant after adjustment with age, sex, body mass index, fasting glucose, triglycerides, and insulin levels, smoking status, 24-h mean systolic BP, high-sensitivity C-reactive protein, estimated glomerular filtration and diuretics use. In logistic regression analysis, the non-dipper - non-dippers were at higher risk of diabetes compared with dipper - dipper group (OR = 2.27, 95% CI: 1.13-4.56, p = 0.022). Conclusions: Our prospective study shows that there is an independent association between non-dipping BP pattern and the incidence of diabetes in a 21-year follow-up.

Life style habits, biochemical factors and their interaction in the prediction of incident hypertension during 21-year follow-up.

BACKGROUND: Hypertension is a global health threat and major cardiovascular risk. Various risk-prediction models for incident hypertension have been developed but not many of them have studied the risk-predictive value of life style factors in combination with cardiovascular biomarkers during long-term period of over 10 years. METHODS: We examined differences in several classical variables for 299 subjects in OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort in subjects with no or new hypertension during a follow-up period of 21 years. Effect of both various life style habits and biomarkers were investigated. RESULTS: Baseline blood pressure, being overweight and smoking actively were independent predictors of new hypertension in majority of multivariate models during long-term follow-up of 21 years in subjects without previous hypertension. Increased high-sensitive C-reactive protein (hsCRP) level (> 3 mg/L) was the strongest predictor of incident hypertension in univariate model. Subjects with two or all three of main risk factors (being overweight, smoking actively and having high hsCRP) had 4-fold risk for incident hypertension. CONCLUSIONS: Smoking, overweight and increased hsCRP level had risk-predictive value in incident hypertension prediction during long-term follow-up of 21 years. Assessment and measurement of these parameters could be used in help of detecting high risk subjects and primary prevention of hypertension very early on. In addition, the study shows that blood pressure at the middle-age should be followed and treated intensively to prevent hypertension in the older age. KEY MESSAGES: Baseline blood pressure, being overweight and smoking actively are independent predictors of new hypertension during a long-term follow-up of 21 years. Having two or all three risk factors (smoking actively, body mass index over 25 kg/m2, high-sensitive C-reactive protein (hsCRP) level over 3 mg/L) indicates a 4-fold risk for incident hypertension within 21-year follow-up.

Assessing Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis: The Simvastatin Ezetimibe in Aortic Stenosis Study (SEAS).

BACKGROUND: Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis is scarce. We used data from the SEAS trial (Simvastatin Ezetimibe in Aortic Stenosis) to assess what blood pressure (BP) would be optimal. METHODS: A total of 1767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease were analyzed. Outcomes were all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. BP was analyzed in Cox models as the cumulative average of serially measured BP and a time-varying covariate. RESULTS: The incidence of all-cause mortality was highest for average follow-up systolic BP ≥160 mm Hg (4.3 per 100 person-years; 95% confidence interval [CI], 3.1-6.0) and lowest for average systolic BP of 120 to 139 mm Hg (2.0 per 100 person-years; 95% CI, 1.6-2.6). In multivariable analysis, all-cause mortality was associated with average systolic BP <120 mm Hg (hazard ratio [HR], 3.4; 95% CI, 1.9-6.1), diastolic BP ≥90 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), and pulse pressure <50 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), with systolic BP of 120 to 139 mm Hg, diastolic BP of 70 to 79 mm Hg, and pulse pressure of 60 to 69 mm Hg taken as reference. Low systolic and diastolic BPs increased risk in patients with moderate aortic stenosis. With a time-varying systolic BP from 130 to 139 mm Hg used as reference, mortality was increased for systolic BP ≥160 mm Hg (HR, 1.7; P=0.033) and BP of 120 to 129 mm Hg (HR, 1.6; P=0.039). CONCLUSIONS: Optimal BP seems to be systolic BP of 130 to 139 mm Hg and diastolic BP of 70 to 90 mm Hg in these patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease or diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Heart rate variability findings as a predictor of atrial fibrillation in middle-aged population.

BACKGROUND: Autonomic nervous system modifies atrial electrophysiologic properties and arrhythmia vulnerability. METHODS: Heart rate (HR) variability, an indicator of cardiac autonomic regulation, was measured in 784 subjects (mean age 51 ± 6 years; 54% males) from a standardized 45-minute period in a study population (n = 1,045), which consisted of randomly selected hypertensive and age- and sex-matched control subjects at the time of recruitment in 1991-1992 (the OPERA study). RESULTS: During a mean follow-up of 16.5 ± 3.5 years, 76 subjects (9.7%) had developed symptomatic atrial fibrillation (AF), needing hospitalization. HR did not predict the occurrence of AF. Among the various spectral and time-domain HR variability indexes, only the low-frequency (LF) spectral component independently predicted AF. In the Cox regression analysis, the hazard ratio of reduced HR corrected LF (LFccv ≤ 1.59%, optimal cutoff from the ROC curve) in predicting the AF was 3.28 (95% CI: 2.06-5.24; P < 0.001). In the multiple Cox regression model, including LFccv and other predictors of AF, such as age, gender, hypertension, history of coronary artery disease, systolic and diastolic blood pressure, body mass index, ß-blocking, angiotensin converting enzyme inhibitor and aspirin medication, left atrial size, left ventricular mass index, and left ventricular size obtained by echocardiography, only LFccv (hazard ratio 2.81; 95% CI: 1.64-4.81; P < 0.001), age (P = 0.006), and systolic blood pressure (P = 0.02) remained as significant predictors of AF. CONCLUSIONS: Impaired LF oscillation of HR predicts new-onset AF in a middle-aged population emphasizing the important role of autonomic nervous system in the genesis of symptomatic AF.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Correction: Smoking cessation and obesity-related morbidities and mortality in a 20-year follow-up study.

[This corrects the article DOI: 10.1371/journal.pone.0279443.].

Non-dipping blood pressure pattern is associated with cardiovascular events in a 21-year follow-up study.

Non-dipping blood pressure (BP) pattern is a predictor for cardiovascular (CV) events and mortality. We evaluated dipping status change and its association with incidence of non-fatal CV events in middle-aged subjects. The OPERA study was carried out during the years 1991-1993, with a follow-up study 21.7 years later. In this study, we included 452 participants with 24-h ambulatory BP measurements (ABPM) available in both surveys. The study population was divided into four groups according to the dipping pattern change: dipping-dipping (n = 152/33.6%), dipping-non-dipping (n = 198/43.8%), non-dipping-dipping (n = 20/4.4%), and non-dipping-non-dipping (n = 82/18.1%). Sixty-five participants experienced a CV event (14.4%) during the 21.7 (SD 0.8) years of follow-up. The incidence of events was highest (28%) in the non-dipping-non-dipping group, and lowest (6.6%) in the dipping-dipping group (p < 0.001). In Cox regression analyses the covariates were age, sex, total cholesterol, hypertension and use of antihypertensive medication, systolic office BP and ambulatory mean or nighttime systolic BP, as well as the change in the variables during the follow-up period. After adjustments, the association of the non-dipping-non-dipping pattern with CV events compared with the dipping-dipping pattern remained significant (HR 4.01; 95% CI 1.89-8.67, p < 0.001). In summary, non-dipping-non-dipping pattern was associated with non-fatal CV events in the long term, and the effect was independent of the conventional risk factors including office and ambulatory BP levels.

Clinical implications of electrocardiographic left ventricular strain and hypertrophy in asymptomatic patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

BACKGROUND: The prognostic impact of ECG left ventricular strain and left ventricular hypertrophy (LVH) in asymptomatic aortic stenosis is not well described. METHODS AND RESULTS: Data were obtained in asymptomatic patients randomized to simvastatin/ezetimibe combination versus placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Primary end point was the first of myocardial infarction, nonhemorrhagic stroke, heart failure, aortic valve replacement, or cardiovascular death. The predictive value of ECG left ventricular strain (defined as T-wave inversion in leads V(4) through V(6)) and LVH, assessed by Sokolow-Lyon voltage criteria (R(V5-6)+S(V1) ≥35 mV) and Cornell voltage-duration criteria {[RaVL+S(V3)+(6 mV in women)]×QRS duration ≥2440 mV · ms}, was evaluated by adjustment for other prognostic covariates. A total of 1533 patients were followed for 4.3±0.8 years (6592 patient-years of follow-up), and 627 cardiovascular events occurred. ECG strain was present in 340 patients (23.6%), with LVH by Sokolow-Lyon voltage in 260 (17.1%) and by Cornell voltage-duration product in 220 (14.6%). In multivariable analyses, ECG left ventricular strain was associated with 3.1-fold higher risk of in-study myocardial infarction (95% confidence interval, 1.4-6.8; P=0.004). Similarly, ECG LVH by both criteria predicted, compared with no ECG LVH, 5.8-fold higher risk of heart failure (95% confidence interval, 2.0-16.8), 2.0-fold higher risk of aortic valve replacement (95% confidence interval, 1.3-3.1; both P=0.001), and 2.5-fold higher risk of a combined end point of myocardial infarction, heart failure, or cardiovascular death (95% confidence interval, 1.3-4.9; P=0.008). CONCLUSIONS: ECG left ventricular strain and LVH were independently predictive of poor prognosis in patients with asymptomatic aortic stenosis. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Plasma lipid levels and body weight altered by intrauterine growth restriction and postnatal fructose diet in adult rats.

BACKGROUND: Intrauterine growth restriction (IUGR) is known to affect the risk of adult diseases. Consumption of lipogenic fructose is increasing, and it is used as an enhancer of metabolic syndrome in rat experiments. The effects of IUGR, postnatal fructose diet, and their interaction on the lipid profile and adiposity were studied in adult rats. METHODS: IUGR was induced by providing pregnant rats with 50% of daily food intake. From 1 mo onward, half of the offspring received a fructose-rich diet and were then followed to the age of 1 and 6 mo, when plasma lipid, glucose, and insulin levels were measured. The adipose tissue was visualized by magnetic resonance imaging at the age of 6 mo. RESULTS: IUGR and fructose diet decreased body weight in adult rats. IUGR increased low-density lipoprotein cholesterol in 6-mo-old rats. The fructose diet evoked hypertriglyceridemia and hyperinsulinemia in both the sexes and decreased fasting glucose levels in female rats. Postnatal fructose diet increased lipid content percentage in the retroperitoneal and intra-abdominal adipose tissues in male rats. Interactions between IUGR and postnatal fructose diet were observed in adult weight in males. CONCLUSION: These results demonstrate the importance of IUGR and fructose diet in adverse changes in lipid and glucose metabolism.

Peptide hormones in infants with feeding disorders.

The prevalence of eating problems in otherwise healthy infants is a common problem in Western countries. Peptide hormones such as adiponectin, ghrelin and resistin have been shown to play an important role in the regulation of satiety and hunger in several diseases and states. The aim of this study was to evaluate the peptide hormone levels in children with eating problems. In this study, 12 otherwise healthy infants (mean age 10.4 months) with eating problems and 12 healthy controls were studied. At their first hospital visit samples for analysis of adiponectin, ghrelin and resistin were obtained and a careful physical examination was carried out. To exclude any possible anatomic or metabolic reason for eating problems necessary investigations were also performed. Adiponectin levels were significantly higher in the cases than in the controls (p = 0.033), and the difference was still significant after adjustment for weight (p < 0.05). Resistin and ghrelin concentrations showed no significant differences. Conclusions. For the first time we were able to show in this pilot study that adiponectin concentrations were elevated in the infants with eating problems. Cross-sectional association does not necessarily imply causal relationship. Thus, further studies with larger number of cases will be needed to clarify the role of adiponectin in the eating problems in infants.

Leisure time and occupational physical activity, overall and cardiovascular mortality: a 24-year follow-up in the OPERA study.

BACKGROUND: In earlier studies, the health benefits of physical activity have only been related to leisure time physical activity (LTPA). High occupational physical activity (OPA) might even be harmful. The current physical activity recommendations do not separate the OPA and LTPA. We investigated the effect of LTPA and OPA on cardiovascular morbidity and mortality during long-term follow-up. We also examined how heavy work affects the benefits of leisure time exercise. MATERIAL AND METHODS: The study was part of the OPERA study and the baseline examinations were conducted between the years 1991 and 1993. The Follow-up of events continued until the end of the year 2020. Study subjects (n = 1044) were divided into four groups according to their LTPA ("no exercise", "irregular", "regular" and "heavy regular") and into three groups according to their OPA ("no activity", "mild" and "heavy"). The amount of exercise was self-reported and the exercise status was defined at the beginning of the study. Study subjects were followed up for their overall mortality (26 years), fatal and non-fatal CVD events (24 and 20 years) and heart failure (20 years). The survival analysis was performed using Kaplan-Meier curves and Cox-proportional hazard models. RESULTS: "Heavy" OPA group subjects belonging to the "irregular" (less than 1-2 times 30 min exercise per week) LTPA group experienced the lowest overall mortality compared to other LTPA groups. Also, overall mortality was increased in the "mild" (p = 0.002) and CVD mortality in the" heavy" (p = 0.005) OPA group compared to "no activity". The incidence of heart failure was increased in the "no exercise" LTPA compared to the "heavy regular" (p = 0.015) group. CONCLUSIONS: Study subjects who were in physically demanding occupations (heavy OPA) seemed to benefit from less LTPA than WHO currently recommends. Thus we suggest targeting different LTPA recommendations to different OPA groups.

Overall mortality was increased in the "mild" and CVD mortality in the" heavy" OPA group compared to "no activity" OPA in 26-year follow-up.Study subjects in physically demanding occupations benefitted more from less LTPA than the WHO currently recommends.High LTPA protected middle-aged study subjects from heart failure compared with sedentary study subjects at 20-year follow-up.

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial.

Background: High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. Methods: In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint. Findings: Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, -0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18-1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23-2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event. Interpretation: hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Funding: Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Outcome of patients with low-gradient "severe" aortic stenosis and preserved ejection fraction.

BACKGROUND: Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area < 1.0 cm² and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient "severe" stenosis (defined as aortic valve area < 1.0 cm² and mean gradient ≤ 40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. METHODS AND RESULTS: Outcome in patients with low-gradient "severe" aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm²; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67 ± 10 years; ejection fraction, ≥ 55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182 ± 64 versus 212 ± 68 g; P < 0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P = 0.37; major cardiovascular events, 50.9% versus 48.5%, P = 0.58; cardiovascular death, 7.8% versus 4.9%, P = 0.19). Low-gradient severe stenosis patients with reduced stroke volume index (≤ 35 mL/m²; n = 223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P = 0.53). CONCLUSIONS: Patients with low-gradient "severe" aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Adiponectin concentration in plasma is associated with muscle fiber size in healthy middle-aged men.

Obesity and ectopic fat deposition are major risk factors for many diseases ranging from insulin resistance to type 2 diabetes and atherosclerosis. In obese individuals, the size of muscle fibers is increased mainly because of the ectopic fat present in skeletal muscle. The aim of the study was to investigate if adipokines would associate with muscle fiber characteristics and if muscle fiber characteristics and expression of the skeletal muscle adiponectin receptor (ADIPOR) would be associated with overweight and other components of the metabolic syndrome. This is a population-based, epidemiological cross-sectional study where normotensive, non-smoking men with normal OGTT provided a muscle biopsy (N = 54). Body mass index was higher in the group with the largest muscle fiber size (p for trend < 0.05) compared to medium (p < 0.05) or small (p < 0.05) muscle fiber size. Plasma adiponectin level (p < 0.05) was negatively and concentrations of leptin (p < 0.05) and hs-CRP (p < 0.05) positively associated with muscle fiber size before adjustments. The inverse association between the plasma adiponectin level and muscle fiber size tertile remained significant (p < 0.05) when adjusted for age and total adiposity. No associations were observed between the expression of muscle adiponectin receptors (ADIPOR) and features of the metabolic syndrome. Skeletal muscle fiber characteristics are related to overweight. In addition, a correlation was observed between low adiponectin and large muscle fiber size and this was not dependent on the amount of total fatness.