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Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46-76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008-1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008-1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001-1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

Background: The association between leisure-time physical activity (LTPA) and the risk of sudden cardiac death (SCD) in coronary artery disease patients is not well known. We aim to assess whether there is an association between LTPA and the risk of SCD and non-SCD in patients with coronary artery disease., Methods: Patients with angiographically verified coronary artery disease (n=1946) underwent a clinical evaluation, including filling in an LTPA questionnaire and extensive risk profiling at the baseline. The patients were classified into 4 groups according to LTPA: (1) inactive; (2) irregularly active; (3) active, exercise regularly 2× to 3× weekly; (4) highly active, exercise regularly ≥4× weekly. Age, sex, body mass index, left ventricular ejection fraction, type 2 diabetes mellitus, history of myocardial infarction, Canadian Cardiovascular Society grading of angina pectoris class, and exercise capacity were used as covariates in the multivariate Cox regression analysis., Results: During follow-up (median 6.3 years), 52 SCDs and 49 non-SCDs occurred. Inactive patients had increased risk for SCD compared with active patients (hazard ratio, 2.45 [95% CI, 1.01-5.98]; P <0.05). A significant LTPA×Canadian Cardiovascular Society grading of angina pectoris class interaction was observed in SCD risk ( P =0.019 in highly active patients). LTPA was not associated with SCD in patients with Canadian Cardiovascular Society grading of angina pectoris class 1 (n=1107, 18 events). Among patients with Canadian Cardiovascular Society grading of angina pectoris class 2 or higher (n=839, 34 events), increased risk for SCD was encountered in highly active patients (hazard ratio, 7.46 [95% CI, 2.32-23.9]; P <0.001) and inactive patients (hazard ratio, 3.64 [95% CI, 1.16-11.5]; P <0.05) as compared to active patients. A linear association was observed between LTPA and non-SCD; those with high LTPA had the lowest risk for non-SCD., Conclusions: Inactive coronary artery disease patients had increased risk for SCD. In subgroup analysis among symptomatic patients, the risk of SCD was increased in highly active and inactive patients compared with active patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01426685.

Background: Prediabetes has proven to have many unfavourable impacts on the cardiovascular system. Methods: The OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study included 1045 middle-aged subjects followed from the years 1990-1993 to 2014. The focus was on peptide hormones. Results: Plasma resistin levels were higher among prediabetics ( p  = .001), particularly impaired glucose tolerance (IGT) ( p  < .001), but not impaired fasting glucose (IFG) patients than among normal glucose tolerance (NGT) or diabetes groups. Diabetics showed lower resistin levels than IGT subjects ( p  < .001). IGT or diabetes groups showed lower adiponectin and higher leptin levels compared to the NGT group ( p  < .001). The IFG group had the highest blood pressure and left ventricular mass index, even higher than the diabetic group. Diabetics had the highest, prediabetics (IFG + IGT) intermediate and NGT the lowest risk for CVD events during follow-up ( p  < .001). Among prediabetics, high plasma ghrelin was an independent predictor of CVD events ( p  < .05) in the Cox regression analysis although it did not significantly improve either classification or discrimination of the patients. Conclusions: Among glucose tolerance groups, patients with IGT had the highest resistin, but equally high leptin and low adiponectin levels as diabetics. Among prediabetics, ghrelin seems to predict independently cardiovascular events in the long term.KEY MESSAGEAmong glucose tolerance groups, patients with IGT had the highest resistin, but equally high leptin and low adiponectin levels as diabetics.Among prediabetics, ghrelin seems to predict independently cardiovascular events in the long term.

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 (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.

Aims: To investigate prognostic significance of post-exercise recovery of rate-pressure product (RPP) in patients with stable coronary artery disease (CAD) and type 2 diabetes (T2D)., Methods: Patients with angiographically documented CAD and T2D (n = 697) underwent symptom-limited bicycle exercise test. Exercise capacity (EC), heart rate, blood pressure and RPP responses to peak exercise and recovery (2' and 5' after cessation of exercise) were analyzed. Cardiac death was the primary and sudden cardiac death (SCD) secondary endpoint., Results: During a median follow-up of 76 months, 49 cardiac deaths (7.0%) and 28 SCDs (4.0%) were observed. The recovery of RPP at 5' was the strongest univariate predictor of cardiac death (hazard ratio [HR]: 2.55 per SD decrease, 95%CI: 1.82-3.58, p < 0.001) and SCD (HR: 2.34, 95%CI: 1.51-3.62, p < 0.001). In multivariate analysis, it remained significantly associated to cardiac death and SCD without (HR: 1.66, 95%CI: 1.14-2.41, p < 0.01 and HR: 1.75, 95%CI: 1.08-2.85, p < 0.05, respectively) and with additional adjustment for EC and peak RPP (HR: 1.45, 95%CI: 1.09-1.92, p < 0.05 and HR: 1.52, 95%CI: 1.01-2.27, p < 0.05, respectively)., Conclusions: The recovery of RPP after exercise is a potent predictor of cardiac death in patients with CAD and T2D. It provides significant prognostic information beyond EC and peak RPP., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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/m 2 , high-sensitive C-reactive protein (hsCRP) level over 3 mg/L) indicates a 4-fold risk for incident hypertension within 21-year follow-up.

We investigated the effect of two-year home-based exercise training program on oxidized low-density lipoprotein LDL (ox-LDL) and high-density lipoprotein HDL (ox-HDL) lipids in patients with coronary artery disease (CAD), both with and without type-2 diabetes (T2D). Analysis of lipoprotein-oxidized lipids was based on the determination of baseline conjugated dienes in lipoprotein lipids. In order to study the effect of an exercise load on ox-LDL and ox-HDL lipids patients in both CAD and CAD + T2D intervention, groups were divided in three based on exercise load (high, medium, and low). During the two-year home-based exercise training program, the study showed that only higher training volume resulted in a decreased concentration of ox-LDL, while the two groups with lower training volumes showed no change. This result indicates that the training load needs to be sufficiently high in order to decrease the concentration of atherogenic ox-LDL lipids in patients with CAD and CAD + T2D. Interestingly, the concentration of ox-HDL did not change in any of the subgroups. This could indicate that the lipid peroxide-transporting capacity of HDL, suggested by results from exercise training studies in healthy adults, may not function similarly in CAD patients with or without T2D. Moreover, the lipid-lowering medication used may have had an influence on these results.

Introduction: Relation between atrial fibrillation (AF) and cancer is known but not very well understood. The purpose of this prospective study was to find out whether subjects with cancer were at greater risk of AF than subjects without cancer., Materials and Methods: The study was based on the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) material and had 1045 subjects and the mean follow-up time of 16.3 years. During the follow-up AF and cancer diagnosis were made (atrial flutter included) if these events were listed in the National Death Registry and/or hospital discharge registry., Results: In this study 130 subjects (12%) had cancer and 19% of these had AF, whereas only 9% of those without cancer experienced AF during the follow-up (p<0.001). Subjects in the cancer group had greater probability of developing atrial fibrillation during the follow-up time in comparison to the subjects without cancer (Hazard ratio (HR) 2.47 (95%CI) 1.57-3.88) in multivariate model including relevant confounding factors., Conclusion: The main finding of this OPERA study was that cancer is an independent risk factor of atrial fibrillation. Still it remains unclear whether this association is causative or whether cancer and atrial fibrillation just share the same pathophysiologic mechanisms., Competing Interests: The authors have declared that no competing interests exist.

Aims: Biomarkers have shown promising results in risk assessment of cardiovascular events. Their role in predicting the risk of sudden cardiac death (SCD) is not well established. We tested the performance of several biomarkers in risk assessment for SCD in patients with coronary artery disease (CAD) and preserved left ventricular function., Methods and Results: The study population consisted of 1,946 CAD patients (68% male; mean age 66.9±8.6 yrs; type 2 diabetes (T2D) 43%) enrolled in the ARTEMIS study. The study subjects underwent examinations with echocardiography and measurement of several biomarkers. The primary endpoint of the study was SCD. During the mean follow up of 76±20 months 50 patients experienced SCD. Elevated high sensitive CRP (hs-CRP, p = 0.001), soluble ST2 (sST2, p<0.001), B-type natriuretic peptide (BNP, p<0.001), and highly sensitive TroponinT (hs-TnT, p<0.001) predicted the occurrence of SCD in univariate analysis. Using the optimal cutoff points, elevated sST2 (≥27.45ng/mL; hazard ratio [HR] 2.7; 95%CI 1.4-5.1, p = 0.003) and hs-TnT (≥15 ng/mL; HR 2.9; 95% CI 1.5-5.6, p = 0.002) were the strongest predictors of SCD followed by hs-CRP (HR 2.4; 95% CI 1.3-4.4, p = 0.004) and BNP (HR 1.9; 95% CI 1.0-3.7, p = 0.046) in adjusted analysis. Combination of elevated hs-TnT and sST2 resulted in adjusted HR of 6.4 (95% CI 2.6-15.5, p<0.001)., Conclusion: Elevated sST2 and hs-TnT predict the occurrence of SCD among patients with CAD and preserved left ventricular function. The association between sST2, hs-TnT and SCD may be explained by an ongoing myocardial apoptosis followed by fibrosis leading to vulnerability to malignant arrhythmias., Competing Interests: The authors have declared that no competing interests exist.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes an enormous burden to human health and health-care systems all over the world. A great proportion of this burden results from increased risk of cardiovascular diseases. Atrial fibrillation (AF) is the most common chronic heart arrhythmia globally and it increases the risk of embolic stroke and heart failure. Recent studies have explored the association between NAFLD and AF with somewhat conflicting results. However, ultrasound-verified prospective studies concur that NAFLD is associated with the incidence of AF. According to epidemiological evidence, the greater the prevalence of NALFD in a population, the stronger the association with AF incidence and prevalence. Specifically, diabetic individuals with NAFLD are at the greatest risk of AF. Additionally, the risk of AF may concentrate most in individuals with advanced NAFLD, particularly those with liver fibrosis. The possible mechanistic factors between NAFLD and AF, particularly obesity and systemic inflammation, are diverse and form a complex interplaying network. However, further studies are needed to elucidate whether NAFLD has a causative role in the development of AF. The purpose of this article is to review and discuss the epidemiologic evidence and possible mechanistic links between these two conditions. KEY MESSAGES Although epidemiologic studies have provided conflicting results on the association of NAFLD and AF, prospective studies with ultrasound-verified NAFLD concur that NAFLD is associated with about 2-fold greater incidence of AF among general population and about 6-fold greater incidence among subjects with type 2 diabetes. The risk of AF among individuals with NAFLD is increased by other cardiovascular risk factors, especially type 2 diabetes and advanced age. The possible mechanistic links between NALFD and AF are diverse, with obesity and systemic inflammation having a significant role, but further studies are needed until NAFLD can be established as a causal factor in the incidence of AF.

Background: The influence of autonomic cardiac regulation on long-term risk of new-onset atrial fibrillation (AF) in coronary artery disease (CAD) is not well established., Objective: The purpose of this study was to evaluate the value of heart rate variability, a marker of cardiac autonomic regulation, in predicting new-onset AF in CAD., Methods: The Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection study population consisted of 1946 patients with CAD. After exclusions, the present analysis included 1710 patients. Those patients had a 24-hour electrocardiographic recording at baseline., Results: A total of 143 cases (8.4%) of new-onset AF were observed during a follow-up of 5.6 ± 1.5 years. The lower values of the short-term scaling exponent of the detrended fluctuation analysis (DFA1) and the ratio of the low-frequency and high-frequency components of the power spectrum (LF/HF ratio) remained the strongest heart rate variability predictors of the development of AF after relevant adjustments in Cox multivariate regression analysis (P < .001 for both). The accuracy of these parameters in prediction of AF was even better (area under the receiver operating characteristic curve 0.630 and 0.631, respectively) than that of echocardiographic left atrial diameter (area under the curve 0.618). Including DFA1 and LF/HF ratio in the AF risk model increased the C-index from 0.630 (95% confidence interval 0.569-0.692) to 0.666 (95% confidence interval 0.612-0.720)., Conclusion: Impaired cardiac autonomic regulation measured by DFA1 and LF/HF ratio predicts the development of new-onset AF as well as or even better than left atrial diameter in patients with CAD., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Antibodies to phosphocholine and oxidized LDL (oxLDL) are proposed to modify progression of atherosclerosis. We investigated the prognostic value of antibodies to phosphocholine (PCho), Streptococcus pneumoniae cell wall polysaccharide (CWPS) and oxLDL in defining long-term CVD survival., Methods: CVD incidence was followed for 18 years and analyzed with baseline plasma IgM, IgG and IgA antibody levels to PCho, CWPS and oxLDL in 1044 subjects of Oulu Project Elucidating Risk of Atherosclerosis study (OPERA)., Results: During the follow-up period, 195 subjects (18.7%) had a CVD event. Cox model with ACC/AHA CVD adjustments (ASCVD) showed that IgA levels to PCho and IgA to CWPS were statistically significant factors predicting CVD risk. IgM and IgG antibodies to PCho, CWPS and oxLDL had no effect on CVD risk after adjusting for other risk factors. Net reclassification improvement (categories: 17-year risk <15%, 15-30%, >30%), was 0.06 (-0.001-0.12, p < 0.054), and IDI was 0.0124 (0.0036-0.0211, p < 0.006) with IgA-PCho added to the ASCVD risk model. Seventeen (9.4%) study subjects with CVD events were correctly reclassified into higher risk category while 9 (5.0%) subjects were classified into lower risk category. Among the non-cases, 58 (8.7%) subjects were correctly reclassified into lower risk, and 46 (5.9%) were reclassified into higher risk category., Conclusions: Plasma IgA antibodies to PCho and Streptococcus pneumoniae CWPS are significant predictors of long-term CVD risk. Additional studies on the role of IgA antibodies in atherogenesis and CVD are warranted., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To examine trends in incidence and 28-day case fatality of myocardial infarction (MI) in persons aged 75-99 years in four areas of Finland., Methods and Results: The Finnish Acute Myocardial Infarction (FINAMI) register is a population-based MI register study, which during 1995-2012 recorded 30561 suspected acute coronary syndromes in persons aged ≥75 years. Of them, 16229 fulfilled the American Heart Association criteria for a definite, probable or possible MI or coronary death. This age-group contributed 56.8% of all MIs of which 62.7% occurred in women. The incidence of MI decreased by -3.3%/year (95% CI -4.2; -2.4) in women aged 75-84 years, and by -1.2%/year (-1.9; -0.5) in women aged 85-99 years, but among men in these age-groups, only a non-significant reduction occurred. The 28-day case fatality of MI was high. In the age-group 75-84 years, it decreased non-significantly by -1.6%/year in men, and significantly by -2.4%/year (-3.9; -0.8) in women. In the age-group 85-99 years, the decrease was more remarkable: -5.1%/year (-7.8; -2.3) and -3.9%/year (-5.5; -2.2), respectively., Conclusions: In Finland, more than half of MIs occur in the age-group 75-99 years, and most of them in women. The incidence of MI decreased significantly in elderly women but non-significantly in elderly men. The 28-day case fatality decreased especially in the age-group 85-99 years. Key Messages In Finland, more than one half of all myocardial infarctions (MIs) occur in the age-group of 75 years or older. Furthermore, 62.7% of MIs among elderly patients occur among women, although 58.0% of the elderly population are women. The incidence of MI decreased significantly in elderly women but not in elderly men. The 28-day case fatality in elderly patients was high but decreased significantly during the study period 1995-2012. This study provides population-based data on treatment strategies and trends in incidence, event rate, mortality and case fatality of MI in elderly individuals. Elderly patients with acute coronary syndromes still present a remarkable burden to the healthcare system in Finland as well as in many other developed countries. Especially considering the modern trend of reducing hospital resources and shifting patient care to outpatient clinics, the epidemiology of MI in elderly patients remains an important issue for the future planning of the healthcare system.

Background: The data on biomarkers as predictors of atrial fibrillation (AF) in patients with coronary artery disease (CAD) are limited., Methods: A total of 1946 patients with CAD were recruited to the ARTEMIS study. At baseline, the study patients underwent clinical and echocardiographic examinations and had laboratory tests. The patients (n=1710) with the information about the occurrence of new-onset AF during the follow-up were included in the present analysis., Results: During 5.7±1.5years of follow-up, 143 (8.4%) patients developed a new-onset AF. Higher values of soluble ST2 (sST2) (20.2±10.8 vs. 17.5±7.2ng/mL, p=0.005), high-sensitivity troponin T (hs-TnT) (11.9±10.2 vs. 10.3±8.3ng/L, p=0.005), high-sensitivity C-reactive protein (hs-CRP) (3.3±5.9 vs. 2.0±4.4mg/L, p<0.001) and brain natriuretic peptide (BNP) (85.6±77.5 vs. 64.9±73.5ng/L, p<0.001) had significant associations with the occurrence of new-onset AF. In the Cox clinical hazards model, higher age (p=0.004), greater weight (p=0.045), larger left atrial diameter (p=0.001), use of asthma/chronic obstructive pulmonary disease medication (p=0.001) and lack of cholesterol lowering medication (p=0.008) had a significant association with the increased risk of AF. When the biomarkers were tested in the Cox clinical hazards model, sST2 (HR=1.025, 95% CI=1.007-1.043, p=0.006) and hs-CRP (HR=1.027, 95% CI=1.008-1.047, p=0.006) retained their significant power in predicting AF., Conclusion: A biomarker of fibrosis, sST2, and a biomarker of inflammation, hs-CRP, predict the risk of occurrence of new-onset AF in patients with CAD. These biomarkers contributed to the discrimination of the AF risk model, but did not improve it markedly., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The significance of premature atrial contraction (PAC) count and supraventricular runs (SVR) for the risk of development of new-onset atrial fibrillation (AF) in patients with coronary artery disease (CAD) is not well established., Methods: The Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study cohort consisted of 1,946 patients with CAD who underwent clinical and echocardiographic examinations, 24-hour ambulatory ECG monitoring, and laboratory tests. After excluding patients who were not in sinus rhythm at baseline or were lost from the follow-up, the present study included 1,710 patients. SVR was defined as at least four PACs in a row with a duration <30 seconds., Results: During a follow-up for an average 5.6 ± 1.5 years, new-onset AF was identified in 143 (8.4%) patients. In the univariate analysis, both SVR and PAC count were associated with the development of new-onset AF. When SVR and PAC count were adjusted with the established AF risk markers of the modified CHARGE-AF model in the Cox multivariate regression analysis, both parameters remained significant predictors of the occurrence of new-onset AF (HR = 2.529, 95 % CI = 1.763-3.628, P ˂ 0.001 and HR = 8.139 for ≥1,409 PACs [the fourth quartile] vs. ≤507 PACs [the first quartile], 95 % CI = 3.967-16.696, P ˂ 0.001, respectively). Together these parameters improved the C-index of the established AF risk model from 0.649 to 0.718, P < 0.001., Conclusion: Including SVR and PAC count to the established AF risk model improves the discrimination accuracy in predicting AF in patients with CAD., (© 2017 Wiley Periodicals, Inc.)

Introduction: Leptin is an adipose tissue-derived hormone associated with cardiovascular risk factors. We examined whether leptin predicts major adverse cardiac events (MACE) in coronary artery disease (CAD) patients., Methods: Fasting plasma leptin levels were measured in 1327 male and 619 female CAD patients. The patients were followed up for two years. The primary endpoint (MACE) was the composite of a hospitalisation for congestive heart failure (CHF) or a cardiac death. The secondary endpoint was the composite of an acute coronary syndrome (ACS) or a stroke., Results: In regression analysis including established risk variables, high leptin levels were associated with a significantly increased risk of MACE (HR 3.37; 95%CI 1.64-6.90; p = 0.001) and ACS or stroke (HR 1.95; 95%CI 1.29-2.96; p = 0.002). Adding leptin to the risk model for MACE increased the C-index from 0.78 (95%CI 0.71-0.85) to 0.81 (0.74-0.88) and improved classification (NRI 0.36; 95%CI 0.13-0.60; p = 0.002) and discrimination of the patients (IDI 0.016; 95%CI 0.001-0.030; p = 0.031)., Conclusions: High plasma leptin levels predict short-term occurrence of CHF or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible harmful effects of leptin should be thoroughly investigated. Key messages Leptin is a peptide hormone secreted mainly by adipose tissue. It has been associated with several cardiovascular risk factors. High leptin levels predict the short-term occurrence of congestive heart failure or cardiac death and ACS or stroke in patients with CAD independently of established risk factors. The possible detrimental effects of leptin on the cardiovascular system should be thoroughly investigated.

Background: The data on cardiac remodeling outside the scope of myocardial infarction and heart failure are limited. Methods: A cohort of middle-aged hypertensive subjects with age- and gender-matched control subjects without hypertension ( n = 1,045, aged 51 ± 6 years) were randomly selected for the OPERA study (Oulu Project Elucidating Risk of Atherosclerosis study). The majority of those who were still alive after more than 20 years of follow-up underwent thorough re-examinations. Results: Left ventricular mass index (LVMI) increased significantly from 106.5 ± 27.1 (mean ± SD) to 114.6 ± 29.1 g/m 2 ( p < 0.001), the thickness of the left ventricular posterior wall (LVPW) from 10.0 ± 1.8 to 10.6 ± 1.7 mm ( p < 0.001), fractional shortening (FS) from 35.0 ± 5.7 to 38.4 ± 7.2 % ( p < 0.001), and left atrial diameter (LAD) from 38.8 ± 5.2 to 39.4 ± 6.7 mm ( p = 0.028) during the 20-year follow-up. After multivariate adjustments, hypertension treated with antihypertensive medication and male gender predicted a smaller increase in the thickness of LVPW ( p = 0.017 to <0.001). Baseline higher fasting plasma insulin level, larger intima media thickness of the carotid artery, greater height and antihypertensive medication ( p = 0.046-0.002) predicted a smaller (less favorable) change of FS. The increase of LAD was associated with higher baseline diastolic blood pressure ( p = 0.034) and greater height ( p = 0.006). Conclusion: Aging from middle age to senescence increases the echocardiographic indexes of LVMI, LVPW thickness, FS and LAD. Several baseline factors are associated with these changes.

Background: Chronic liver injury from different etiologies drives liver fibrosis. However, little is known about the associated factors, systemic factors in particular. Recently, non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation have been shown to be associated with each other. Thereby, we aimed to study the association between atrial fibrillation and liver stiffness., Study: Extensive clinical measurements including echocardiography of the heart, transient elastography (TE) of the liver and the presence of atrial fibrillation were determined in elderly Finnish study subjects (n = 76, mean age 73 years) from OPERA (Oulu Project Elucidating the Risk of Atherosclerosis) study cohort. Half of the study subjects had non-alcoholic fatty liver disease, whereas others did not have any known hepatic morbidity. The present study was cross-sectional by nature., Results: The subjects with atrial fibrillation had higher TE values (with atrial fibrillation TE = 9.3kPa, without atrial fibrillation TE = 6.3kPa, p = 0.018). When the cohort was divided to four subgroups (those without NAFLD or atrial fibrillation, with NAFLD but without atrial fibrillation, with both conditions, and with atrial fibrillation but without NAFLD), the TE value was the highest in the subjects with both conditions (5.3kPa, 7.4kPa, 10.8kPa and 7.8kPa, respectively, p = 0.019). Moreover, the higher the TE value, the more prevalent atrial fibrillation was (the atrial fibrillation prevalence by tertiles of TE 27% / 36% / 77%, p = 0.001). Likewise, the greater the TE value, the greater the left atrial diameter, a collateral of atrial fibrillation (left atrial diameters by tertiles of TE 39mm / 45mm / 48mm, p<0.001) was. All these p-values for continuous variables remained statistically significant even after adjustment for common clinically relevant risk factors., Conclusions: There is an association between atrial fibrillation and liver stiffness. This novel association may have multiple explanations and mechanistic links, which are discussed here and need further studies, prospective studies in particular.

Background: We hypothesized that elevated nighttime systolic ambulatory blood pressure (ABP) yields additional information compared with daytime systolic ABP for the long-term risk of atrial fibrillation (AF) and perhaps should be taken into account in treatment strategies for preventing the increasing burden of AF during aging., Methods: A total of 903 subjects with or without hypertension aged 40 to 59 years, who were recruited to the Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study, underwent ABP monitoring, thorough clinical examinations and laboratory tests., Results: After an average of 16.4 ± 3.6 years of follow-up, 91 (10%) of the study subjects had experienced a new-onset AF requiring a hospital emergency room or hospital visit. Of the components of baseline ABP, the nighttime mean systolic blood pressure had the strongest univariable association with the occurrence of AF (120.8 ± 15.9 vs. 116.4 ± 14.1 mm Hg, P = 0.006, in subjects with vs. without the occurrence AF). When the univariable predictors of AF, such as age, sex, body mass index, height, smoking history, alanine aminotransferase, uric acid, and fasting plasma glucose, were entered in the multivariable Cox hazards model, age (P < 0.001), and body mass index (P = 0.014) retained their significant predictive power. After adjustments in this clinical hazards model, the nighttime mean systolic blood pressure still predicted the occurrence of AF (hazards ratio = 1.07 per every 5 mm Hg increase, 95% confidence intervals = 1.004-1.15, P = 0.038)., Conclusion: Of the baseline ABP characteristics, the nighttime systolic blood pressure is a significant independent contributor to the long-term risk of new-onset AF requiring a hospital visit., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Two Universities from Oulu, Finland organised integrated and interprofessional (IP) type 2 diabetes training periods for undergraduate medical and nursing students in collaboration with the University Hospital and Health and Wellbeing Centre of Oulu. There is an ongoing health, social services and regional government reform in Finland. The services will be organised in a customer-orientated way and the reform will combine the primary and secondary services. The training was tailored to reflect the real life future setting in Finnish primary care, and this model fits well with the principles of collaborative education. The study aimed at investigating students' attitudes and readiness for inter professional learning and their learning experience in combined primary and secondary care settings. The second aim was to strengthen students' professional skills by working with patients in a patient-centred manner. The "Readiness for Interprofessional Learning Scale" was used with added questions about pair training. Students' perceptions of their clinical skills were evaluated. The students valued the mutual learning experience in outpatient primary care. They felt comfortable with working together and complemented each other. Students performed well with IP competencies such as patient centredness, communication and team functioning. Patients in general were very satisfied with the visit. Teamwork and collaboration, professional identity and pair work were highly scored in both student groups while roles and responsibilities were evaluated a little less positively. Collaboration between different levels of care and health policies is important when developing health professionals' education. This IP teamwork experience helps both future and current health-care professionals to better organise the care of chronic illnesses., Competing Interests: No potential conflict of interest was reported by the authors.

Background Coronary heart disease incidence, mortality and short-term case-fatality have improved substantially during the past decades. Recent changes in the long-term prognosis among survivors of acute coronary syndrome are less well known. Our aim was to investigate the long-term prognosis of acute coronary syndrome. Design An observational myocardial infarction register study. Methods Data was derived from the population based Finnish Myocardial Infarction register. Patients aged 35 or higher, who had their first acute coronary syndrome during 1993-2011 and survived the first 28 days, were included in the analysis ( n = 13,336). Endpoints were fatal and non-fatal cardiovascular disease events and all-cause mortality at one year and three years after the index event. We also compared the prognosis of acute coronary syndrome survivors with the prognosis of an apparently healthy population with the same age, sex and area of residence, derived from the FINRISK study. Results Significant declines over time were observed in the risk of a new cardiovascular disease event. At three year follow-up the age- and study area-adjusted hazard ratio per calendar year was 0.969 (95% confidence interval 0.960-0.977, p = 4.63 × 10 -13 ) among men and 0.969 (95% confidence interval 0.961-0.978, p = 1.01 × 10 -11 ) among women. Despite the improvement in prognosis, the age-standardized three year cardiovascular disease free survival of acute coronary syndrome patients was significantly lower than in the FINRISK control group (for men p = 6.64 × 10 -27 and for women p = 2.11 × 10 -15 ). Conclusion The prognosis of acute coronary syndrome survivors has improved during the 18-year period but is still much worse than the prognosis of comparable general population.

Background: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are both shown to increase the risk of cardiovascular diseases and type 2 diabetes. However, there is a great overlap between these two diseases. The present study was aimed to examine the cardiovascular and metabolic prognosis of non-alcoholic fatty liver disease with and without metabolic syndrome., Methods: Middle-aged subjects (n=958) were divided into four subgroups, those with NAFLD and MetS, those with NAFLD or MetS, and healthy controls. The baseline characteristics of the subgroups were analyzed. The follow-up time for cardiovascular events was about 16years. After approximately 21years the cardiac ultrasound and laboratory parameters were re-analyzed and new type 2 diabetes cases were recorded., Results: Those with both diseases were at the greatest risk for cardiovascular events (p<0.001). Compared to healthy controls, only those with MetS, with or without NAFLD, were at increased risk for the development of type 2 diabetes (p<0.001) and for an increase in left ventricular mass index (p=0.001 and p=0.005, respectively). The cardiovascular and metabolic risk in subjects with NAFLD only was quite similar to that in healthy controls. The I148M variant of the patatin-like phospholipase domain-containing 3 gene (PNPLA3 polymorphism) was most present in those with NAFLD only (p=0.008)., Conclusions: NAFLD with MetS implies a considerable risk for cardiovascular diseases, type 2 diabetes and the increase of left ventricular mass index whereas NAFLD without MetS does not., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS., Study Design and Main Outcome Measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses., Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk., Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to test the hypothesis that novel biomarkers may predict cardiac events in diabetic patients with stable coronary artery disease (CAD). Serum levels of highly sensitive troponin T (hs-TnT), B-type natriuretic peptide, highly sensitive C-reactive protein (hs-CRP), galectin-3, and soluble suppressor of tumorigenicity-2 (sST2) were analyzed in 1,137 patients with CAD and with type 2 diabetes, impaired glucose tolerance, or fasting glycaemia (diabetic group) and in 649 patients with normal glucose state. Cardiac death or hospitalization for congestive heart failure was the major end point during the follow-up of 2 years. Forty patients in the diabetic group (3.5%) and 9 patients in the nondiabetic group (1.4%) reached the primary end point. High hs-TnT level (≥14 ng/l) was the strongest predictor of the primary end point with hazard ratio of 24.5 (95% confidence interval 8.7 to 69.0; p <0.001) and remained so when adjusted for clinical variables, ejection fraction, renal, lipid, and glycemic status and other biomarkers (hazard ratio 9.9, 95% confidence interval 3.2 to 30.8; p <0.001). In the multivariate model, hs-CRP, B-type natriuretic peptide, and sST2 also predicted the primary end point in the diabetic group (p <0.01 for all). Only sST2 (p <0.001) and hs-CRP (p = 0.02) predicted the primary end point in nondiabetic group. The inclusion of hs-TnT in the model significantly improved discrimination (integrated discrimination improvement 0.050) and reclassification of the patients (net reclassification index 0.21). In conclusion, hs-TnT is a strong predictor of cardiac death or hospitalization for heart failure independently from traditional risk markers or other biomarkers in diabetic patients with stable CAD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ghrelin is a peptide hormone from the stomach, with an ability to release growth-hormone from the pituitary. Numerous cross-sectional studies indicate that ghrelin also has a role in metabolic abnormalities, such as metabolic syndrome and type 2 diabetes, but evidence for long-term effect is scarce. We investigated, whether ghrelin concentration measured in middle age would predict the development or absence of metabolic disturbances subsequently. Study population consisted of 600 middle-aged persons, and the follow-up time was approximately 21 years. Plasma total ghrelin concentration was measured at the baseline, and divided to tertiles. Numerous anthropometric and other clinical measurements (including blood pressure), and laboratory test were made both at the baseline and at the follow-up. After the follow-up the prevalence of high systolic blood pressure according to MetS IDF-criteria was the lowest in the highest ghrelin tertile, and the highest in the first (p<0.03). When only subjects free of hypertension medication at baseline were considered, subjects belonging to the highest ghrelin tertile developed less new hypertension and high blood pressure according to IDF-criteria as well as medication for it during the follow-up (p<0.05). Although serum insulin levels were negatively correlated to ghrelin levels at both points in time (p<0.001 at baseline and p=0.003 at follow-up), plasma ghrelin concentration did not predict the development of abnormalities in glucose tolerance. The association with ghrelin and metabolic syndrome was lost during the follow-up. In conclusion, our results suggest high ghrelin to be protective against the development of hypertension in the long-term follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are widespread diseases and have multiple common risk factors and comorbidities. No studies of association between ultrasonography-diagnosed NAFLD and AF exist in other than diabetic population. The goal of this prospective study was to study the value of NAFLD as a predictor of atrial fibrillation. This study had 958 subjects from the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort, and the mean follow-up time was 16.3 years. NAFLD was diagnosed if the subject had fatty liver in ultrasonography and no excess alcohol intake. AF was followed in the National Registers. In this study 249 subjects (26.0%) had NAFLD and 37 (14.9%) of these had AF whereas only 56 (7.9%) of those without NAFLD experienced AF during the follow-up time (p = 0.001). In the multiple Cox regression analysis including potential confounders (age, sex, study group, diabetes, body mass index (BMI), waist circumference, alcohol consumption, smoking, serum alanine aminotransferase concentration (ALT), systolic blood pressure, quick index, left ventricular mass index, left atrial diameter, coronary artery disease (CAD), atrial natriuretic peptide (ANP) and high sensitive C-reactive protein (hs-CRP)), NAFLD remained as an independent predictor of AF (Adjusted OR, 1.88 (95% Confidence interval (CI) 1.03-3.45)). In conclusion, our data shows that NAFLD is independently associated with the risk of AF.

Although exercise capacity (EC) and autonomic responses to exercise predict clinical outcomes in various populations, they are not routinely applied in patients with coronary artery disease (CAD). We hypothesized that the composite index of EC and exercise heart rate responses would be a powerful determinant of short-term risk in CAD. Patients with angiographically documented stable CAD and treated with β blockers (n = 1,531) underwent exercise testing to allow the calculation of age- and gender-adjusted EC, maximal chronotropic response index (CRI), and 2-minute postexercise heart rate recovery (HRR, percentage of maximal heart rate). Cardiovascular deaths and hospitalization due to heart failure, registered during a 2-year follow-up (n = 39, 2.5%), were defined as the composite primary end point. An exercise test risk score was calculated as the sum of hazard ratios related to abnormal (lowest tertile) EC, CRI, and HRR. Abnormal EC, CRI, and HRR predicted the primary end point, involving 4.5-, 2.2-, and 6.2-fold risk, respectively, independently of each other. The patients with intermediate and high exercise test risk score had 11.1-fold (95% confidence interval 2.4 to 51.1, p = 0.002) and 25.4-fold (95% confidence interval 5.5 to 116.8, p <0.001) adjusted risk for the primary end point in comparison with the low-risk group, respectively. The addition of this risk score to the established risk model enhanced discrimination by integrated discrimination index and reclassification by categorical and continuous net reclassification index (p <0.001 for all). In conclusion, the composite index of EC and heart rate responses to exercise and recovery is a powerful predictor of short-term outcome in patients with stable CAD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Factors in the middle age that are associated with the risk for development of diastolic dysfunction in long term are not fully established. The Oulu Project Elucidating Risk of Atherosclerosis OPERA study randomly selected middle-aged subjects with hypertension and age- and gender-matched control subjects (n = 1,045, age 51 ± 6 years, men 49.8%). After >20 years of follow-up, majority of the subjects still alive were available for reexaminations (n = 600). After excluding the subjects with mitral regurgitation, left ventricular ejection fraction <50%, and those from whom echocardiographic septal E/E' could not be reliably measured, the present analysis included 460 subjects. E/E' was divided into 3 subgroups (subgroup 1: E/E' ≤8, subgroup 2: 8 < E/E' < 15, subgroup 3: E/E' ≥15), subgroup 3 suggesting a significant diastolic dysfunction. Several baseline variables were associated with diastolic dysfunction: greater age (p = 0.001), female gender (p = 0.001), shorter height (p <0.001), larger body mass index (p = 0.008), greater systolic blood pressure (p = 0.001), greater pulse pressure (p <0.001), lower baroreflex sensitivity (p = 0.007), lower estimated glomerular filtration rate (p = 0.02), greater atrial natriuretic peptide (p = 0.001), greater fasting plasma glucose (p = 0.001), more common occurrence of diabetes (p = 0.011), and more common usage of antihypertensive medication (p = 0.001). After adjustments in the multivariate model, only systolic blood pressure (p = 0.001), shorter height (p = 0.002), and estimated glomerular filtration rate (p = 0.006) retained a significant association with the risk of developing diastolic dysfunction. In conclusion, greater systolic blood pressure, short height, and lower estimated glomerular filtration rate of the middle-aged subjects were the main determinants of development of diastolic dysfunction during a 20-year follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To compare the effects of constructivism-based dietary group counseling transmitted through videoconferencing (VC) and face-to-face (FF) counseling on changes in eating behaviors., Methods: Altogether, 74 participants with high risk of type 2 diabetes were divided into FF and VC groups based on their place of residence in northern Finland. Constructivism-based dietary group counseling, a nonrandomized intervention, was performed (evaluations at 0, 6, and 21 months). The Three-Factor Eating Questionnaire-18 was used to evaluate cognitive restraint eating (CR), emotional eating (EE), and uncontrolled eating (UE). Data were analyzed using ANOVA and ANCOVA (significance level of 0.05)., Results: Cognitive restraint eating increased and UE decreased between baseline and 6 months in both groups, but between baseline and 21 months only in the FF group (P = .005 and P = .021, respectively). Emotional eating decreased only in the VC group (P = .016). There were no differences between groups at 6 or 21 months., Conclusions and Implications: Constructivism-based counseling delivered through videoconferencing was effective at improving eating behaviors., (Copyright © 2015 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Background/objectives: The association of dietary sodium and cardiovascular disease (CVD), as well as the reduction of sodium intake in the prevention of CVD, has been under debate. To study whether sodium consumption has a role as a risk factor for fatal and non-fatal CVD., Subjects/methods: A well-defined population-based cohort of 1045 subjects collected between 1991 and 1993 (mean age 51.4 years) was used with approximately 19 years' follow-up. At the baseline, 716 subjects filled in a 1-week food follow-up diary, which was used to calculate the daily sodium intake (mg/1000 kcal)., Results: The baseline sodium intake correlated significantly with age (rs=0.117, P=0.002), BMI (rs=0.216, P=0.000), waist circumference (rs=0.268, P=0.000), smoking (rs=0.144, P=0.000), alcohol consumption (rs=0.111, P=0.003), systolic blood pressure (rs=0.106, P=0.005) and low-density lipoprotein (LDL) cholesterol (rs=0.081, P=0.033). Those who had cardiovascular events in the follow-up consumed more sodium at the baseline (mean 2010.4 mg/1000 kcal/day, s.d. 435.2, n=101) compared with the subjects without events (mean 1849.9 mg/1000 kcal/day, s.d. 361.2, n=589; t-test; P=0.001). The incidence of cardiovascular events was greater in the highest quartile (22.1%) than in the lower quartiles (first 11.0%, second 9.9% and third 15.6%; X(2); P=0.005). Cox regression analysis showed that sodium intake as a continuous variable predicts CVD events (P=0.031) independently when age, sex, smoking, alcohol consumption, systolic blood pressure, LDL cholesterol and waist circumference were added as covariates. This predictive role is seen especially in the group of subjects on hypertensive medication (P=0.001)., Conclusions: Dietary sodium intake is a significant independent predictor of cardiovascular events in the study population.

Purpose of Review: The increasing prevalence of metabolic syndrome and the consequent cardiovascular diseases has stimulated an active search for novel risk factors. The hormones regulating energy balance are of special interest as potential risk factor indicators of cardiovascular diseases. Ghrelin provides an attractive target for studies of atherosclerosis being a gastric peptide hormone having multiple functions including orexigenic and growth hormone-releasing effects and is also involved in the regulation of cardiovascular and immunomodulatory system., Recent Findings: The aim of the present article is to review recent studies on the role of ghrelin in the atherosclerosis. Ghrelin seems to influence known risk factors of atherosclerosis, endothelial dysfunction, inflammation and oxidation. These themes will be covered by the present article and a summary of clinical studies of ghrelin in atherosclerosis will be given., Summary: Ghrelin plays a beneficial role in multiple processes of atherogenesis and vascular function. However, ghrelin's effects are not as strong as those of traditional known risk factors.

We tested the hypothesis that acute post-exercise change in blood pressure (BP) may predict exercise training responses in BP in patients with coronary artery disease (CAD). Patients with CAD (n = 116, age 62 ± 5 years, 85 men) underwent BP assessments at rest and during 10-min recovery following a symptom-limited exercise test before and after the 6-month training intervention (one strength and 3-4 aerobic moderate-intensity exercises weekly). Post-exercise change in systolic BP (SBP) was calculated by subtracting resting SBP from lowest post-exercise SBP. The training-induced change in resting SBP was -2 ± 13 mmHg (p = 0.064), ranging from -42 to 35 mmHg. Larger post-exercise decrease in SBP and baseline resting SBP predicted a larger training-induced decrement in SBP (β = 0.46 and β = -0.44, respectively, p < 0.001 for both). Acute post-exercise decrease in SBP provided additive value to baseline resting SBP in the prediction of training-induced change in resting SBP (R(2) from 0.20 to 0.26, p = 0.002). After further adjustments for other potential confounders (sex, age, baseline body mass index, realized training load), post-exercise decrease in SBP still predicted the training response in resting SBP (β = 0.26, p = 0.015). Acute post-exercise change in SBP was associated with training-induced change in resting SBP in patients with CAD, providing significant predictive information beyond baseline resting SBP.

Objective and Methods: The impact of the rs9939609 FTO variant on cardiovascular events was investigated in the 19-year follow-up of subjects recruited to the OPERA study., Results: A total of 212 cardiovascular disease (CVD) and 152 coronary heart disease (CHD) events or deaths occurred during follow-up. The logistic regression analysis revealed that among the AA genotype the incidence of CHD (OR 1.905; 95% CI 1.250-2.903, p = 0.001) and CVD (OR 1.849; 1.265-2.702, p = 0.003) events or death was significantly higher when adjusted for age, sex, and study group. After further adjustment with BMI, smoking status, systolic blood pressure, and low-density lipoprotein cholesterol, the higher incidence of CHD and CVD events or death among subjects with the AA genotype remained significant (OR 1.895; p = 0.002 and p = 0.004, respectively). In Cox regression analysis, the AA genotype displayed a higher rate of CVD and CHD death when the model was adjusted for sex, age, and study group (p = 0.006 and p = 0.046). FTO rs9939609 AA genotype improved the C-index of the final predictive model from 0.709 to 0.715. In reclassification analyses, the integrated discrimination index was significant 0.011 (p = 0.010)., Conclusion: The AA genotype of FTO rs9939609 seems to be associated with a higher risk of CVD, and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.

The aim of our investigation was to find out if ghrelin concentrations or polymorphisms predict the future risk for cardiovascular diseases and cancer in a population-based cohort initiated in 1991 (491 hypertensive and 513 control subjects). Total mortality and hospital events were followed up for 19 years. Fasting total ghrelin concentrations were determined and Arg51Gln, Leu72Met and -501 A > C polymorphisms identified. Cox regression analysis was performed. The mean value in the control cohort was 674 pg/ml whereas in the hypertensive cohort it was 661 pg/ml. The associations found suggest that in the controls the highest ghrelin quartile protected from CHD (coronary heart disease). The results were significant without or with adjustments for age, sex, smoking, systolic blood pressure and LDL cholesterol, BMI, type 2 diabetes or QUICK index. C/C variant of the promoter associated with the prevention of IHD (ischemic heart disease) in the hypertensive group (p<0.05). The controls with the Leu72Leu genotype had less cancer (p<0.05). In conclusion, high plasma ghrelin concentration was related to protection from CHD and Leu72Leu genotype to prevention of cancer in healthy adults during the 19 years follow-up. C/C promoter protects from IHD in the hypertensive subjects., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Highly prevalent metabolic syndrome (MS) is a major public health problem worldwide. Insulin resistance and central obesity are postulated to be the key components of this metabolic syndrome, and inflammation also plays a role in cardiovascular events. In previous years, many definitions of metabolic syndrome have emerged., Design and Methods: The value of MS as a predictor of cardiovascular events in median 18-year follow-up was studied in a prospective study cohort that included 1004 Finnish males and females. Cardiovascular disease included major coronary heart disease and stroke (excluding subarachnoid hemorrhage)-whichever of these happened first., Results: Subjects with metabolic syndrome had a 2.01-fold (95% CI 1.46-2.77) higher probability for any cardiovascular event compared with subjects with no MS. hsCRP seemed to increase the risk prediction, whereas adiponectin was not helpful. Those having five components of MS had hazard ratios of 7.89 (2.26-27.60) for any cardiovascular event in the follow-up when compared with those having no components and adjusting by traditional risk factors (p < 0.01)., Conclusions: MS is an important predictor of cardiovascular events and is most harmful in combination with high plasma hsCRP. The clustering of components is especially harmful., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Depressed baroreflex sensitivity (BRS) is associated with an increased risk of mortality in patients with a known cardiac disease. The prognostic significance of BRS in subjects without history of major cardiovascular (CV) events is unknown. The present study tested the hypothesis that impaired BRS predicts the CV mortality in a population-based sample of middle-aged subjects. The present study is a part of the Oulu Project Elucidating Risk of Atherosclerosis study, where middle-aged hypertensive and age- and gender-matched control subjects were randomly selected. Along with clinical and laboratory assessments, BRS was measured from the blood pressure overshoot of Valsalva maneuver in 559 subjects (age 51 ± 6 years; 300 men). The causes of death (n = 72) were registered during a follow-up of up to 19 years. CV death (n = 23) was defined as the primary end point. CV death was predicted by smoking status, alcohol consumption, high-sensitivity C-reactive protein, use of diuretics, waist circumference, and fasting glucose. Among all measured risk factors, impaired Valsalva BRS (<3 ms/mm Hg) was the most potent predictor of CV death (hazard ratio 9.1, 95% confidence interval 3.8 to 21.7, p <0.001) and remained so after adjustments for the other significant predictors (hazard ratio 5.3, 95% confidence interval 2.1 to 13.3, p <0.001). In conclusion, impaired Valsalva BRS is a potent and independent predictor of CV death in a population-based sample of middle-aged subjects without history of major CV complications and may have important clinical implications in early risk stratification., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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, β-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., (© 2014 Wiley Periodicals, Inc.)

Objective: We investigated if the differences in liver fat content would predict the development of non-fatal and fatal atherosclerotic endpoints (coronary heart disease and stroke)., Design, Setting and Participants: Our study group is a population-based, randomly recruited cohort (Oulu Project Elucidating Risk of Atherosclerosis, OPERA), initiated in 1991. The cohort consisted of 988 middle-aged Finnish participants., Intervention: Total mortality and hospital events were followed up to 2009 based on the registry of the National Institute for Health and Welfare and the National death registry., Main Outcome Measure: The severity of hepatic steatosis was measured by ultrasound and divided into three groups (0-2). Cox regression analysis was used in the statistical analysis., Results: In the follow-up of years 1991-2009, 13.5% of the participants with non-fatty liver, 24.2% of participants having moderate liver fat content and 29.2% of the participants having severe fatty liver experienced a cardiovascular event during the follow-up time (p<0.001). Severe liver fat content predicted the risk for future risk of cardiovascular event even when adjusted for age, gender and study group (HR 1.92, CI 1.32 to 2.80, p<0.01). When further adjustments for smoking, alcohol consumption, low-density lipoprotein-cholesterol, body mass index and systolic blood pressure were conducted, the risk still remained statistically significant (HR 1.74, CI 1.16 to 2.63, p<0.01). Statistical significance disappeared with further adjustment for QUICKI., Conclusions: Liver fat content increases the risk of future cardiovascular disease event in long-term follow-up but it is seems to be dependent on insulin sensitivity.

Two leptin receptor single nucleotide polymorphisms, Lys109Arg and Gln223Arg, have been shown to associate with several risk factors for cardiovascular disease. In addition, we have previously shown that Arg109 and Arg223 homozygotes displayed lower intima-media thickness in our well-defined OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. This current research investigated the impact of these LEPR polymorphisms on cardiovascular events and related death as well as to total mortality in the 19-year follow-up of OPERA. Subjects were randomly selected, middle-aged drug-treated hypertensives and their age- and sex-matched control subjects recruited to the OPERA study between 1990 and 1993. Mortality and hospital events of 1045 subjects were followed up until 2009. A total of 151 coronary heart disease (CHD) and 211 cardiovascular disease (CVD) events or deaths including 58 CHD and 69 CVD deaths occurred. Furthermore, during this follow-up, a total of 165 subjects died. Logistic regression analysis was performed to assess the impact of Lys109Arg and Gln223Arg on the events and death. Further modeling was performed with Cox regression for Lys109Arg. The logistic regression analysis revealed a significant protective impact of Arg109Arg genotype on CHD (OR 0.433; CI 95% 0.217-0.863) and CVD (OR 0.540; CI 95% 0.309-0.942) events or death as well as on total mortality (OR 0.390; CI 95% 0.196-0.775) when adjusted with age, sex and study group. Even after further adjustment with BMI, smoking status, systolic blood pressure and low-density lipoprotein cholesterol, the protective effect of Arg109Arg on CHD events or death and total mortality still remained statistically significant (OR 0.463; CI 95% 0.230-0.931 and OR 0.442; CI 95% 0.218-0.896, respectively). Arg109Arg was also shown to confer protection against CHD mortality (HR 0.224; CI95% 0.055-0.919) and overall mortality (HR 0.413; CI95% 0.218-0.783) also in Cox regression analysis. In conclusion, the Arg109Arg genotype of LEPR seems to be protective from cardiovascular events and death and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis., (© 2013 Elsevier B.V. All rights reserved.)

Type 2 diabetes (T2D) has shown limited impact on cardiac autonomic function in patients with cardiac disease at rest. The effect of T2D on autonomic responses to sympathetic stimuli, such as passive tilt and static exercise, is not well known in patients with coronary artery disease (CAD). Heart rate, arterial pressure, and their variability along with baroreflex sensitivity (BRS) were analyzed at supine rest and during passive head-up tilt (TILT) and static handgrip exercise (HG) in CAD patients with (T2D+, n=68, 61±6 years, 14 women) and without T2D (T2D-, n=68, 62±6 years, 17 women). The effect of T2D at rest and in responses to TILT and HG was examined. In T2D+, the normalized low-frequency (0.04-0.15 Hz) power of R-R intervals was higher at rest (44±17 vs. 38±17 nu, p=0.015) and its response to TILT and HG was lower than that in T2D- (8±21 vs. 2±17 nu, p=0.041 and 3±18 vs. -4±15 nu, p=0.019, respectively). Vagally mediated heart rate variability indices and BRS were not different between T2D+ and T2D-. We concluded that T2D has a specific impact on low-frequency oscillation of R-R interval among patients with angiographically documented CAD. This may indicate increased basal sympathetic modulation of sinoatrial node and lower sympathetic responsiveness to sympathetic activation by baroreceptor unloading and exercise pressor response. Limited effects of T2D on vagally mediated heart rate variability and baroreflex were observed in the patients with CAD., (© 2013.)

Aim: Obesity and type 2 diabetes (T2D) associate with increased oxidative stress. Malondialdehyde acetaldehyde (MAA) adducts have been suggested to be one of the antigenic epitopes in MDA-LDL responsible for the antibody recognition. Our aim was to investigate the associations between plasma IgA antibodies to MAA-LDL, inflammatory markers, adipokines, obesity, and T2D., Methods: IgA to MAA-LDL were measured in a subsample (n = 1507) of the Finnish Health 2000 survey. The associations between antibody levels, obesity, TNF-α, IL-6, high-sensitivity (hs) CRP, resistin, adiponectin, fasting plasma (fp) glucose, fp-insulin, glycosylated hemoglobin (Hb-A1C), and T2D were investigated., Results: IgA to MAA-LDL associated positively with fasting plasma insulin. IgA to MAA-LDL were higher among subjects with T2D (P < 0.001) compared to subjects with normal glucose metabolism. IgA to MAA-LDL associated with obesity, but was not independently (P = 0.002, not significant after correction for multiple tests) associated with T2D in logistic regression analysis. IgA to MAA-LDL, obesity, and TNF-α all associated with markers of glucose metabolism., Conclusions: T2D subjects had increased IgA to MAA-LDL compared to subjects with normal glucose metabolism. The data suggest that the associations between IgA to MAA-LDL and markers of glucose metabolism were independent of TNF-α but dependent on components of the metabolic syndrome.

Long-term fructose consumption has been shown to evoke leptin resistance, to elevate triglyceride levels and to induce insulin resistance and hepatic steatosis. Autophagy has been suggested to function in processes such as lipid storage in adipose tissue and inflammation in liver. Autophagy and the leptin system have also been suggested to regulate each other. This study aimed to identify the changes caused by fetal undernourishment and postnatal fructose diet in the gene expression of leptin, its receptors (LEPR-a, LEPR-b, LEPR-c, LEPR-e and LEPR-f) and autophagy genes in the white adipose tissue (WAT) and liver of adult male rats in order to clarify the mechanism behind the metabolic alterations. The data clearly revealed that the long-term postnatal fructose diet decreased leptin levels (p < 0.001), LEPR (p < 0.001), especially LEPR-b (p = 0.011) and LEPR-f (p = 0.005), as well as SOCS3 (p < 0.001), ACC (p = 0.006), ATG7 (p < 0.001), MAP1LC3β (p < 0.001) and LAMP2 (p = 0.004) mRNA expression in WAT. Furthermore, LEPR (p < 0.001), especially LEPR-b (p = 0.001) and LEPR-f (p < 0.001), ACC (p = 0.010), ATG7 (p = 0.024), MAP1LC3β (p = 0.003) and LAMP2 (p < 0.001) mRNA expression in the liver was increased in fructose-fed rats. In addition, the LEPR expression in liver and MAP1LC3β expression in WAT together explained 55.7 % of the variation in the plasma triglyceride levels of the rats (R adj. (2)  = 0.557, p < 0.001). These results, together with increased p62 levels in WAT (p < 0.001), could indicate decreased adipose tissue lipid storing capacity as well as alterations in liver metabolism which may represent a plausible mechanism through which fructose consumption could disturb lipid metabolism and result in elevated triglyceride levels.

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.

Recent genome-wide association studies have identified genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRSs) constructed of these variants would predict incident cardiovascular disease (CVD) events. We genotyped 32 common single nucleotide polymorphisms in several Finnish cohorts, with up to 32,669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. We created GRSs separately for systolic BP and diastolic BP by multiplying the risk allele count of each single nucleotide polymorphism by the effect size estimated in published genome-wide association studies. We performed Cox regression analyses with and without adjustment for clinical factors, including BP at baseline in each cohort. The results were combined by inverse variance-weighted fixed-effects meta-analysis. The GRSs were strongly associated with systolic BP and diastolic BP, and baseline hypertension (all P<10(-62)). Hazard ratios comparing the highest quintiles of systolic BP and diastolic BP GRSs with the lowest quintiles after adjustment for age, age squared, and sex were 1.25 (1.07-1.46; P=0.006) and 1.23 (1.05-1.43; P=0.01), respectively, for incident coronary heart disease; 1.24 (1.01-1.53; P=0.04) and 1.35 (1.09-1.66; P=0.005), respectively, for incident stroke; and 1.23 (1.08-1.40; P=2 × 10(-6)) and 1.26 (1.11-1.44; P=5 × 10(-4)), respectively, for composite CVD. In conclusion, BP findings from genome-wide association studies are strongly replicated. GRSs comprising bona fide BP-single nucleotide polymorphisms predicted CVD risk, consistent with a lifelong effect on BP of these variants collectively.

Objective and Methods: The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance., Results: Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics., Conclusion: A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.

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.

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.

Aims: We investigated the association between daily sodium intake and each individual component of the metabolic syndrome (MS) as well as the metabolic cluster per se and clarified which of the combinations of MS features is particularly associated with sodium intake., Methods: A total of 716 subjects from our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort were selected to fill in a food follow-up diary for a 1-week period. The MS was determined using the International Diabetes Federation (IDF) criteria., Results: Subjects with the MS used more sodium (P < 0.001), less carbohydrate (P < 0.001), less fibre (P = 0.031), and more alcohol (P < 0.001) than those without the MS. High sodium intake was strongly related to elevated BMI (P = 0.003), waist (P < 0.001), and higher fasting blood glucose (P < 0.001). The subjects with the highest sodium intake suffered more often from type 2 diabetes (P = 0.007). Sodium intake was highest in the group where all the MS criteria were present (P < 0.001). High sodium intake was a statistically significant predictor of the MS in logistic regression analysis (P = 0.009). The highest sodium intake was observed in the IDF criteria combination waist + glucose + blood pressure., Conclusions: These findings suggest that a reduction in sodium intake may be especially beneficial in the treatment of individuals with the MS.