Search

Background: Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure-regulating mechanism involving 4β-hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD., Methods and Results: The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4βHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4βHC concentrations. However, in men, high plasma 4βHC was associated with all-cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow-up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6-8.7; P =0.002) and 4.18 (95% CI, 1.5-11.4; P =0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile., Conclusions: High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD., Registration Information: clinicaltrials.gov. Identifier NCT01426685.

The association between lifestyle and cardiac structure and function measures, such as global longitudinal strain and diastolic function in a healthy midlife general population, is not well known. A subpopulation of the Northern Finland Birth Cohort 1966 took part in follow-up, including echocardiography (n = 1,155) at the age of 46. All antihypertensive medication users (n = 164), patients with diabetes (n = 70), subjects with any cardiac diseases (n = 24), and subjects with echocardiography abnormalities (n = 21) were excluded. Moderate to vigorous physical activity (MVPA) was recorded with a wrist-worn accelerometer over 14 days and categorized into high, moderate, and low MVPA groups. Similarly, alcohol consumption was categorized as low, moderate, and high-dose users of alcohol and smoking as nonsmokers, former, and current smokers. The total number of healthy subjects included in the study was 715 (44% males). Left ventricular mass index and left atrial end-systolic volume index were significantly higher in the high MVPA group compared with the low MVPA group (adjusted main effect p = 0.002 and p <0.001, respectively). Cardiac function did not differ among the physical activity groups. High alcohol consumption was associated with impaired global longitudinal strain and diastolic function (adjusted main effect p = 0.002 and p = 0.004, respectively) but not with any cardiac structure variables. Smoking was not associated with cardiac structure or function. In healthy middle-aged adults, MVPA was independently associated with structural changes in the heart but not with cardiac function. High alcohol consumption was associated with impaired modern cardiac function measures but not with cardiac structure., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We studied the association between participation in the longitudinal follow-up study and cardiometabolic disorders in two longitudinal studies which started prospectively in the antenatal period: the Northern Finland Cohort 1966 (NFBC1966) and the Northern Finland Birth Cohort 1986 (NFBC1986). Both birth cohorts have been followed up since birth with multiple follow-ups including questionnaires, and clinical examinations., Methods: The NFBC studies were compared to comparison cohorts of individuals who were born in the same area as the study cohorts, but in different years. The data for the comparison cohort were obtained from registers. The cumulative incidence rates of hospital-treated cardiometabolic disorders were calculated for study and comparison cohorts covering the age of 7-50 years in NFBC1966 and the age of 0-29 years in NFBC1986. Cardiometabolic-related causes of death were analysed in NFBC1966 and the comparison cohort from the age of 0-50 years. The analysed cardiometabolic disorders were diabetes mellitus, coronary artery disease, hyperlipidaemia, obesity, hypertension, and cerebrovascular disorders. The risk ratio (RR) with 95% confidence intervals (CI) was calculated by sex., Results: In NFBC1966, no differences in cumulative incidences of cardiometabolic disorders or cardiometabolic-related deaths compared to the comparison cohort were found. Male members of NFBC1986 had decreased risk of obesity (RR: 0.45, 95% CI: 0.27-0.75) and any cardiometabolic disorders (RR: 0.75, 95% CI: 0.59-0.95) compared to the comparison cohort., Conclusions: The results suggest that participation in the NFBC1986 may have a weak positive health effect among men. Agreement to follow-up studies focusing on diet, substance use, and physical activity, may slightly decrease the incident risk of cardiometabolic disorders in the study population.KEY MESSAGESEven mild interventions, such as follow-up studies in the prospective follow-up studies, might affect participants' behaviour and consequently the incidence of cardiometabolic disordersThe fact that follow-up itself might affect the study population in terms of risk factors, has to be taken into account when estimating the representativeness of the followed population.

The aim of this study was to cross-sectionally examine whether hemoglobin (Hb) levels within the normal variation associate with heart rate variability (HRV) measures and baroreflex sensitivity (BRS). The study population included 733 Finnish subjects of the OPERA cohort (aged 41-59 yr, 53% males, 51.7% treated for hypertension) of whom HRV was measured from a standardized 45-min period and whose Hb levels were within the Finnish reference intervals. The low Hb tertile (mean Hb, 135 g/L) had an overall healthier metabolic profile compared with the high Hb tertile (mean Hb, 152 g/L). BRS was higher in the low Hb tertile compared with the high Hb tertile ( P < 0.05). R-R interval (RRi) and standard deviation (SD) of the RRi (SDNN)index were the longest in the low Hb tertile regardless of posture. Of the spectral components of HRV, HF power was the highest in the low Hb tertile regardless of posture ( P < 0.05). In a stepwise logistic regression model, BRS associated negatively with Hb levels after adjusting for covariates ( B = -0.160 [-0.285; -0.035]). Similar associations were observed for SDNNindex when lying down ( B = -0.105 [-0.207; -0.003]) and walking ( B = -0.154 [-0.224; -0.083]). For HF power negative associations with Hb levels were observed when lying down ( B = -0.110 [-0.180; -0.040]), sitting ( B = -0.150 [-0.221; -0.079]), and in total analysis ( B = -0.124 [-0.196; -0.053]). Overall, lower Hb levels associated independently with healthier cardiac autonomic function. NEW & NOTEWORTHY Heart rate variability (HRV) and baroreflex sensitivity (BRS), which can be measured noninvasively, can predict cardiac and metabolic diseases. Our findings show that within normal variation subjects with lower hemoglobin (Hb) levels have an overall healthier HRV profile and increased cardiac parasympathetic activity in middle age, independent of age, sex, smoking status, and key metabolic covariates. These findings support our previous findings that Hb levels can be used in assessing long-term risks for cardiometabolic diseases.

Background: All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1., Methods: A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD)., Results: Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5-2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01-0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01-0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD., Conclusions: Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17-82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex.cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts.In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker., (© 2022. The Author(s).)

Pregnane X receptor (PXR) gene variants rs7643645 and rs2461823 are reported to associate with clinically and histologically more severe liver injury in nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Thus, we investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 AA/AG ( n  = 217) or GG ( n  = 27) variants and rs2461823 CC/CT ( n  = 215) or TT ( n  = 27) variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects, 1.676 (1.014-2.772), P  = 0.044. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P  = 0.009. In the subjects without NAFLD ( n  = 731), the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P  = 0.804). There was no difference in the total mortality between the PXR rs2461823 variant subgroups, 1.141 (0.663-1.962; P  = 0.634). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, our result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Further studies are needed to confirm the results of the present study., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Effective treatment and prevention of cardiovascular (CV) diseases requires reliable methods of assessing individual CV event risk. Although standardized risk calculators like Systematic Coronary Risk Evaluation (SCORE) are sufficient in most instances, sometimes more specific clinical examination is needed to determine the most optimal intervention and its intensity., Aim: To study whether carotid and femoral bruits provide prognostic information on CV events, CV mortality and all-cause mortality beyond traditional CV risk factors., Methods: 1045 subjects (49.8% men), aged 51.3 ± 5.97 years were clinically examined in the beginning of 1990's. The subjects were followed for over 20 years and data on CV events and causes of deaths was collected., Results: During the follow-up period, 241 (23.1%) of the subjects died and 82 (34.6%) of the deaths were of CV origin. Carotid bruits were a significant risk factor for CV deaths only if subjects with previous CV events were included. After adjusting for age, sex, systolic blood pressure, smoking, diabetes, LDL cholesterol, coronary artery disease and stroke, carotid bruits posed a hazard ratio (HR) (95% confidence interval) of 4.15 (2.39-8.52) p<0.001 for CV deaths. After excluding subjects with previous CV events (after which n = 941) neither carotid nor femoral bruits were statistically associated with CV events or all-cause mortality. Adding carotid or femoral bruits in the baseline risk model with traditional CV risk factors did not improve C-statistic, reclassification, or discrimination of the subjects., Conclusions: Carotid and femoral bruits do not provide clinically useful information in a pure primary prevention setting. Carotid bruits might be useful in evaluating the overall CV risk in a population where recurrent CV events may occur., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Parkkila et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Obesity and metabolic syndrome (MetS) are known to expose to atrial fibrillation (AF), cardiovascular diseases (CVD) and mortality. Metabolically healthy obesity refers to obesity without MetS. This study aimed to investigate how obesity and MetS modify the risk of CVD, AF and mortality in very long-time follow-up., Methods: Finnish middle-aged subjects ( n  = 1045) were grouped into four subgroups according to the presence of obesity and MetS. CVD events and AF were followed for 24 years and total mortality for 30 years. Moreover, 600 available patients had a follow-up visit for metabolic examinations after approximately 22 years., Results: One-hundred and sixty-two (30%) subjects without obesity or MetS died during the follow-up. Ninety-two (17%) of the patients in this group had a CVD event and 58 (11%) were diagnosed with AF. As compared to them, obese subjects without MetS had similar metabolic fate and mortality (mortality 26 (38%), p  = .143; CVD event 12 (18%), p  = .858 and AF 7 (10%), p  = .912, respectively), whereas subjects with obesity and MetS had greater mortality (102 (49%), p  < .001), more CVD (71 (34%), p  < .001) and AF (49 (23%), p  < .001). Non-obese individuals with MetS had greater rates of mortality (96 (44%), p  < .001) and CVD (80 (37%), p  < .001), but not of AF (26 (12%), p  = .606). Of the 40 subjects with obesity but without MetS at baseline and available for the follow-up visit, 15 (38%) were metabolically healthy at the follow-up visit., Conclusions: In the present long-term follow-up study, the presence of MetS, but not obesity only, implies a greater risk of mortality and CVD. The risk of AF is increased only in subjects with both obesity and MetS. However, obesity without MetS tends to progress eventually to obesity with MetS. Key messagesThe presence of metabolic syndrome (MetS), but not obesity only, entails a greater risk of mortality and cardiovascular diseases.The risk of atrial fibrillation is increased only in subjects with both obesity and MetS.Obesity without MetS tends to progress eventually to obesity with MetS.

Objective: MEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland., Design/methods: We evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985-2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients., Results: There were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm 2 , qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%., Conclusion: In this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients., (© 2022. The Author(s).)

The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nätynki, Leisti, Tuusa, Varpuluoma, Huilaja, Izumi, Herukka, Ukkola, Junttila, Kokkonen and Tasanen.)

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.

Background: To estimate the ability of fasting, 1-h, and 2-h post-load glucose to predict cardiovascular outcomes., Methods: We examined a population-based study consisting of 977 middle-aged subjects who underwent an oral glucose tolerance test with glucose values measured at 0, 60, and 120 min. Participants were followed up to 24 years, and cardiovascular outcomes were collected from national registers. Predictive abilities of fasting, 1-h, and 2-h glucose were evaluated alone and in the prediction models with traditional cardiovascular risk factors using Cox proportional hazard models, the likelihood-ratio test, Harrell's concordance index and integrated discrimination improvement., Results: Cardiovascular endpoint occurred in 222 (22.7%) participants during a median follow-up of 19.8 years. In the prognostic models, 1-h glucose (HR 1.67, 95%CI 1.10-2.53), but not fasting or 2-h glucose, predicted cardiovascular events statistically significantly. In addition, when adding glucose parameters into the model including traditional cardiovascular risk factors, only 1-h glucose improved the predictive ability (LR-test p =.046). Finally, 1-h glucose found slightly over 50% more cardiovascular endpoints that were not recognized by fasting or 2-h glucose levels., Conclusions: Our findings support the earlier ones suggesting that 1-h glucose would be a better long-term predictor of cardiovascular morbidity and mortality than fasting or 2-h glucose.KEY MESSAGESIn addition to conventional CV risk factors,1-h but not fasting or 2-h post-load glucoses seems to be an independent predictor of cardiovascular events and seems to improve the predictive ability of the traditional cardiovascular risk model.Elevated 1-hpost-load glucose finds a large number (slightly over 50%)of cardiovascular endpoints that were not recognized by fasting or 2-h post-load glucose levels.One-hour glucose seems to be a better long-term predictor of cardiovascular morbidity and mortality than fasting or 2-h post-load glucose.

Aims: To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients., Methods: We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993-2011 to identify survivors of first ACS ( n  = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients ( n  = 199)., Results: Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 × 10 -7 ), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 × 10 -15 ), higher Charlson index (p = 1.56 × 10 -19 ) and older age ( p  = .026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization ( p  = .0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication., Conclusion: Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS.

The aim of this study was to cross-sectionally and longitudinally examine whether higher hemoglobin (Hb) levels within the normal variation associate with key components of metabolic syndrome and total and cardiovascular mortality. The study included 967 Finnish subjects (age 40-59 years) followed for ≥ 20 years. The focus was on Hb levels, cardiovascular diseases (CVDs) and mortality rates. Higher Hb levels associated positively with key anthropometric and metabolic parameters at baseline. At the follow-up similar associations were seen in men. The highest Hb quartile showed higher leptin levels and lower adiponectin levels at baseline and follow-up (p < 0.05) and lower plasma ghrelin levels at baseline (p < 0.05). Higher baseline Hb levels associated independently with prevalence of type 2 diabetes at follow-up (p < 0.01). The highest Hb quartile associated with higher serum alanine aminotransferase levels (p < 0.001) and independently with increased risk for liver fat accumulation (OR 1.63 [1.03; 2.57]) at baseline. The highest Hb quartile showed increased risk for total (HR = 1.48 [1.01; 2.16]) and CVD-related mortality (HR = 2.08 [1.01; 4.29]). Higher Hb levels associated with an adverse metabolic profile, increased prevalence of key components of metabolic syndrome and higher risk for CVD-related and total mortality., (© 2021. The Author(s).)

Background and Aims: Both carotid intima-media thickness (IMT) and arterial plaques have been shown to predict future CV events. Since there are no previous studies on the subject, our objective was to compare carotid IMT and the length of plaques in abdominal-pelvic main arteries in CV risk assessment in a prospective study setting with a follow-up of over 20 years., Methods: A total of 1007 patients (50% men), aged 51 ± 6.0 years, participated in the current study. Carotid IMT and the summarized plaque length (SUM) from abdominal aorta to common femoral arteries were ultrasonographically assessed. Patients were followed-up a median (1st-3rd quartile) of 22.5 (17.5-23.2) years for CV events., Results: SUM significantly predicted CV events (HR per every 10 mm increase: 1.035, 95% CI: 1.027-1.044, p < 0.001). Those in the highest SUM tertile had over 3-fold risk for CV event (HR: 3.392, 95% CI: 2.427-4.741, p < 0.001) when compared to those in the lowest tertile. SUM significantly predicted CV events even after adjusting for age, sex, hypertension, diabetes, smoking (pack-years), LDL cholesterol and IMT. Adding SUM to the established model improved C-index (95% CI) from 0.706 (0.674-0.738) to 0.718 (0.688-0.747) as well as both discrimination (p < 0.001) and reclassification (p < 0.001) of the patients. In contrast, IMT predicted cardiovascular events only in univariate analysis and it did not improve discrimination or reclassification of the patients., Conclusions: In light of our findings, SUM is a superior indicator and clinical tool for evaluating the overall CV risk compared to carotid IMT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 contribution of genetic variants to non-ischemic sudden cardiac death (SCD) due to acquired myocardial diseases is unclear. We studied whether SCD victims with hypertension/obesity related hypertrophic myocardial disease harbor potentially disease associated gene variants. The Fingesture study has collected data from 5869 autopsy-verified SCD victims in Northern Finland. Among SCD victims, 740 (13%) had hypertension and/or obesity as the most likely explanation for myocardial disease with hypertrophy and fibrosis. We performed next generation sequencing using a panel of 174 cardiac genes for 151 such victims with the best quality of DNA. We used 48 patients with hypertension and hypertrophic heart as controls. Likely pathogenic variants were identified in 15 SCD victims (10%) and variants of uncertain significance (VUS) were observed in additional 43 SCD victims (28%). In controls, likely pathogenic variants were present in two subjects (4%; p = 0.21) and VUSs in 12 subjects (25%; p = 0.64). Among SCD victims, presence of potentially disease-related variants was associated with lower mean BMI and heart weight. Potentially disease related gene variants are common in non-ischemic SCD but further studies are required to determine specific contribution of rare genetic variants to the extent of acquired myocardial diseases leading to SCD.

Objective: Resistin is a small, cysteine-rich proinflammatory molecule that is primarily secreted by peripheral blood mononuclear cells and macrophages in humans. Previous studies have shown resistin to participate in various pathological processes including atherosclerosis and cancer progression but not many studies have assessed the role of resistin as a risk factor for all-cause mortality. The objective of this prospective study was to evaluate whether resistin predicts mortality among elderly Finnish people., Methods: The study population consisted of 599 elderly (71.7 ± 5.4 years) patients and the follow-up was approximately six years. A thorough clinical examination including anthropometric and other clinical measurements such as blood pressure as well as various laboratory parameters (including resistin) was conducted at baseline., Results: After the follow-up, 65 (11%) of the patients died. Resistin was a significant risk factor for all-cause mortality (HR 3.02, 95% CI: 1.64-5.56, p<0.001) when the highest tertile was compared to the lowest. Resistin remained as a significant risk factor even after adjusting for various covariates such as age, sex, systolic blood pressure, smoking habits, alcohol consumption, medications (antihypertensive, lipid-lowering, glucose-lowering), hsCRP and leisure time physical activity. Receiver operating characteristic (ROC) curve analysis for resistin demonstrated area under the curve (AUC) of 0.656 (95% CI: 0.577-0.734), p<0.001 and an optimal cutoff value of 12.88 ng/ml., Conclusions: Our results indicate that resistin is a significant risk factor for all-cause mortality among elderly Finnish subjects, independent from traditional cardiovascular risk factors., Competing Interests: The authors have declared that no competing interests exist.

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.)

Background and Aims: Obese subjects have elevated leptin levels, which have been associated with increased risk of cardiovascular events. Because leptin has direct cellular effects on various tissues, we tested the hypothesis that leptin levels are associated with cardiac structure or function in patients with coronary artery disease (CAD)., Methods and Results: The study population consisted of 1 601 CAD patients, of whom 42% had type 2 diabetes mellitus. Plasma leptin was measured in fasted state and an echocardiography performed. Leptin levels were not related to LV dimensions or LV ejection fraction (NS for all), but higher leptin levels were associated with elevated E/E' (9.43 vs. 11.94 in the lowest and the highest leptin quartile, respectively; p=0.018 for trend). Correspondingly, a decreasing trend was observed in E/A (1.15 vs. 1.06; p=0.037). These associations were independent of obesity and other relevant confounding variables., Conclusion: We conclude that elevated plasma leptin levels are associated with impaired left ventricular diastolic function in patients with CAD independently of obesity and other confounding variables. Leptin may be one of the mechanistic links explaining the development of congestive heart failure in obese subjects., (Copyright © 2016 Elsevier Inc. 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.)