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

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

Prognostic significance of beat-to-beat variability of spatial heterogeneity of repolarization analyzed from a 5-minute resting electrocardiogram in coronary artery disease.

BACKGROUND: Data on the prognostic significance of temporal variability of spatial heterogeneity of electrocardiographic repolarization in coronary artery disease (CAD) are limited. OBJECTIVE: The purpose of this study was to evaluate the prognostic value of temporal variability of T-wave morphology analyzed from a 5-minute resting electrocardiogram in CAD. METHODS: The standard deviation (SD) of T-wave morphology dispersion (TMD-SD) and the SD of total cosine R-to-T were analyzed on a beat-to-beat basis from a 5-minute period of the standard resting 12-lead electrocardiogram obtained before the clinical stress test in 1702 patients with angiographically verified CAD and well-preserved left ventricular function. RESULTS: During an average of 8.7 ± 2.2 years of follow-up, 60 patients experienced sudden cardiac death/arrest (SCD/SCA) (3.5%), 69 patients nonsudden cardiac death (NSCD) (4.1%), and 161 patients noncardiac death (9.5%). TMD-SD was significantly higher in patients who experienced SCD/SCA than in other patients (1.72 ± 2.00 vs 1.12 ± 1.75; P = .01) and higher in patients who succumbed to NSCD than in other patients (1.57 ± 1.74 vs 1.12 ± 1.76; P = .04), but it did not differ significantly between patients who experienced noncardiac death and those without such an event (1.16 ± 1.42 vs 1.14 ± 1.79; P = .86). In the Cox multivariable hazards model, TMD-SD retained its significant association with the risk of SCD/SCA (hazard ratio 1.119; 95% confidence interval 1.015-1.233; P = .024) but not with the risk of NSCD (hazard ratio 1.089; 95% confidence interval 0.983-1.206; P = .103). CONCLUSION: TMD-SD is independently associated with the long-term risk of SCD/SCA in patients with CAD.

Day-of-the-week variation of sudden unexpected cardiac death.

Background: There has been some controversy about the day-of-the-week (septadian) variation of unexpected sudden cardiac death (SCD). Methods: We evaluated the incidence of unexpected SCD on different days of the week in a consecutive series of 5869 SCD victims from Northern Finland [the FINGESTURE study (Finnish Genetic Study of Arrhythmic Events)]. As it is mandatory in Finland, a medico-legal autopsy was performed on all unexpected sudden death victims. The autopsies were performed between the years 1998-2017. Results: The mean incidence of unexpected SCD was higher at weekends (during the days from Friday to Sunday, peaking on Saturday) than during the days from Monday to Thursday (8.54 ± 0.72 vs. 7.22 ± 0.19 SCDs per day of the week per 100,000 inhabitants per year, p < 0.001). Regardless of sex or ischemic versus non-ischemic etiology of SCD, the distribution of the occurrence of SCD among the days of the week was similar compared with the whole SCD cohort. Conclusion: The incidence of unexpected SCD was highest at weekends (during the days from Friday to Sunday, peaking on Saturday).

Liver X Receptor Agonist 4ß-Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease.

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 4ß-hydroxycholesterol (4ßHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4ßHC 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 4ßHC. 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 4ßHC concentrations. However, in men, high plasma 4ßHC 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 4ßHC quartile. CONCLUSIONS: High plasma 4ßHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4ßHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier NCT01426685.

Lifestyle and Cardiac Structure and Function in Healthy Midlife Population.

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.

Lower hemoglobin levels associate with higher baroreflex sensitivity and heart rate variability.

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.

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

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

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

Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease.

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.

Patients with coronary artery disease (CAD) ­ in which the blood vessels supplying the heart become blocked - need careful management to prevent adverse outcomes related to their disease, such as a heart attack or sudden cardiac death. Identification of markers in the blood to predict adverse outcomes would help to improve the care of patients with CAD. Here, we find that higher circulating levels of endothelin-1 (ET-1), a protein secreted normally to maintain blood pressure, associate with greater risk of death in CAD patients. Cholesterol-lowering statin therapy used at high intensity (high dosage) can counteract the increased risk of death observed in CAD patients with high ET-1. Therefore, circulating ET-1 level could be used as a marker to predict the risk of death in CAD patients, and an indication for high intensity statin therapy. Our findings could help clinicians to improve the management of patients with CAD.

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

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

Causes and characteristics of unexpected sudden cardiac death in octogenarians/nonagenarians.

INTRODUCTION: The risk for sudden cardiac death (SCD) increases with ageing. METHODS: We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims in Northern Finland. All the victims underwent medico-legal autopsy as medico-legal autopsy is mandatory in cases of unexpected sudden death in Finland. All the non-cardiac deaths such as pulmonary embolism and cerebral hemorrhage were excluded from the study, as were unnatural deaths such as intoxications. RESULTS: Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those < 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P < .001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged < 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged < 80 years (P = .001). SCD victims 80 years or older were less likely to die during physical activity than those under 80 years old (5.6% vs. 15.9%, P < .001). Dying in sauna was more common among those ≥ 80 years than among those < 80 years (5.5% vs. 2.6%, P < .001). CONCLUSION: In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged < 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones.

Association between participation in the Northern Finland Birth Cohorts and cardiometabolic disorders.

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.

Association of electrocardiographic spatial heterogeneity of repolarization and spatial heterogeneity of atrial depolarization with left ventricular fibrosis.

AIMS: To evaluate the relationship between spatial heterogeneity of electrocardiographic repolarization and spatial heterogeneity of atrial depolarization with arrhythmic substrate represented by left ventricular fibrosis. METHODS AND RESULTS: We assessed the associations of T- and P-wave morphology parameters analysed from the standard 12-lead electrocardiograms with left ventricular fibrosis in 378 victims of unexpected sudden cardiac death (SCD) who underwent medico-legal autopsy. Based on autopsy findings, the SCD victims were categorized into four different groups according to different stages of severity of left ventricular fibrosis (substantial fibrosis, moderate patchy fibrosis, scattered mild fibrosis, no fibrosis). T-wave and P-wave area dispersion (TWAd: 0.0841 ± 0.496, 0.170 ± 0.492, 0.302 ± 404, 0.296 ± 0.476, P = 0.008; PWAd: 0.574 ± 0.384, 0.561 ± 0.367, 0.654 ± 0.281, 0.717 ± 0.257, P = 0.011, respectively; low values abnormal), non-dipolar components of T-wave and P-wave morphology (T_NonDipolarABS: 0.0496 ± 0.0377, 0.0571 ± 0.0487, 0.0432 ± 0.0476, 0.0380 ± 0.0377, P = 0.027; P_NonDipolarABS: 0.0132 ± 0.0164, 0.0130 ± 0.0135, 0.0092 ± 0.0117, 0.0069 ± 0.00472, P = 0.005, respectively, high values abnormal), T-wave morphology dispersion (TMD: 45.9 ± 28.3, 40.5 ± 25.8, 35.5 ± 24.9, 33.0 ± 24.6, P = 0.030, respectively, high values abnormal), and P-wave heterogeneity (PWH: 20.0 ± 9.44, 19.7 ± 8.87, 17.9 ± 9.78, 15.4 ± 4.60, P = 0.019, respectively, high values abnormal) differed significantly between the groups with different stages of left ventricular fibrosis. After adjustment with heart weight, T_NonDipolarABS [standardized ß (sß) = 0.131, P = 0.014], PWAd (sß = -0.161, P = 0.003), P_NonDipolarABS (sß = 0.174, P = 0.001), and PWH (sß = 0.128, P = 0.015) retained independent association, and TWAd (sß = -0.091, P = 0.074) and TMD (sß = 0.097, P = 0.063) tended to retain their association with the degree of myocardial fibrosis. CONCLUSION: Our findings suggest that abnormal values of T- and P-wave morphology are associated with arrhythmic substrate represented by ventricular fibrosis partly explaining the mechanism behind their prognostic significance.

Pregnane X receptor gene variant rs7643645 and total mortality in subjects with nonalcoholic fatty liver disease.

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.

Prognostic value of P-wave morphology in general population.

AIMS: To evaluate the prognostic significance of novel P-wave morphology descriptors in general population. METHODS AND RESULTS: Novel P-wave morphology variables were analyzed from orthogonal X-, Y-, Z-leads of the digitized electrocardiogram using a custom-made software in 6906 middle-aged subjects of the Mini-Finland Health Survey. A total of 3747 (54.3%) participants died during the follow-up period of 24.3 ± 10.4 years; 379 (5.5%) of the study population succumbed to sudden cardiac death (SCD), 928 (13.4%) to non-SCD (NSCD) and 2440 (35.3%) patients to non-cardiac death (NCD). In univariate comparisons, most of the studied P-wave morphology parameters had a significant association with all modes of death (P from <0.05 to <0.001). After relevant adjustments in the Cox multivariate hazards model, P-wave morphology dispersion (PMD) still tended to predict SCD [hazard ratio (HR): 1.006, 95% confidence interval (CI): 1.000-1.012, P = 0.05) but not NSCD (HR: 0.999, 95% CI: 0.995-1.003, P = 0.68) or NCD (HR: 0.999, 95% CI: 0.997-1.001, P = 0.44). The P-wave maximum amplitude in the lead Z (P-MaxAmp-Z) predicted SCD even after multivariate adjustments (HR: 1.010, 95% CI: 1.005-1.015, P = 0.0002) but also NSCD (HR: 1.005, 95% CI: 1.002-1.009, P = 0.0005) and NCD (HR: 1.002, 95% CI: 1.000-1.005, P = 0.03). CONCLUSION: Abnormalities of P-wave morphology are associated with the risk of all modes of death in general population. After relevant adjustments, PMD was still closely associated with the risk of SCD but not with NSCD or NCD. P-MaxAmp-Z predicted SCD even after adjustments, however, it also retained its association with NSCD and NCD.

Circulating cell-free DNA in health and disease - the relationship to health behaviours, ageing phenotypes and metabolomics.

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.

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

BACKGROUND: Smoking is the biggest preventable factor causing mortality and morbidity and the health benefits of smoking cessation are commonly known. Smoking cessation-related weight gain is well documented. We evaluated the association between smoking cessation and the incidence of obesity-related morbidities such as hypertension, diabetes and metabolic syndrome as well as mortality. We also evaluated telomere length related to smoking cessation. MATERIAL AND METHODS: This study was part of the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. The mean follow up time among the 600 study subjects was 20 years. We divided the study subjects into four groups by smoking status ("never", "current", "ex-smokers" and "quit") and analyzed their health status. "Ex-smokers" had quit smoking before baseline and "quit" quit during the follow-up time. Information about total mortality between the years 2013-2020 was also utilized. RESULTS: During the follow-up time systolic blood pressure decreased the most in the "current" and in the "ex-smoker" groups. Office SBP decreased the least in the "quit" group (p = 0.001). BMI increased the most in the "quit" and the least in the "ex-smokers" group (p = 0.001). No significant increases were seen in the incidence of obesity-related-diseases, such as metabolic syndrome, hypertension and diabetes was seen. There was no significant difference in the shortening of telomeres. Odds of short-term mortality was increased in the "current" group (2.43 (CI 95% 1.10; 5.39)), but not in the "quit" (1.43 (CI 95% 0.73-2.80)) or "ex-smoker" (1.02 (CI 95% 0.56-1.86)) groups when compared to "never" group. CONCLUSIONS: Even though, the blood pressure levels were unfavorable in the "quit" group, there was no significant increase in the incidence of obesity-related-diseases, and a noticeable benefit in short-term mortality was seen during the 6-year follow-up. The benefits of smoking cessation outweigh the disadvantages in the long-term.

Carotid and femoral bruits as cardiovascular risk indicators in a middle-aged Finnish population: A 20-year prospective study.

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.

Use of gliptins reduces levels of SDF-1/CXCL12 in bullous pemphigoid and type 2 diabetes, but does not increase autoantibodies against BP180 in diabetic patients.

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.

Association of atrial depolarization variability and cardiac autonomic regulation with sudden cardiac death in coronary artery disease.

AIMS: To evaluate the prognostic significance of the temporal variability of P-wave morphology, specifically in relation to cardiac autonomic regulation. METHODS AND RESULTS: We analyzed the standard deviation of P-wave residuum (PWRSD) from five consecutive beats of the standard 12-lead ECG in 1236 patients with angiographically verified coronary artery disease (CAD). We evaluated the prognostic value of PWRSD, of PWRSD and PWR in relation to the 24 h standard deviation of normal-to-normal intervals (PWRSD/SDNN and PWR/SDNN). After 8.7 ± 2.2 years of follow-up on average, 43 patients (3.5%) experienced sudden cardiac death (SCD) or were resuscitated from sudden cardiac arrest (SCA), 34 (2.8%) succumbed to non-sudden cardiac death (NSCD) and 113 (9.1%) to non-cardiac death (NCD). In the Cox regression analysis, PWRSD (≥0.002727) had a significant univariate (uv) [hazard ratio (HR): 4.27, 95% confidence interval (CI): 2.26-8.08, P = 0.000008] and multivariate (mv) (HR: 2.58, 95% CI: 1.31-5.08, P = 0.006) association with SCD/SCA but not with NSCD (uv P = 0.76, mv P = 0.33) or NCD (uv P = 0.57, mv P = 0.66). All the studied P-morphology parameters retained a significant association with the risk of SCD/SCA after relevant adjustment (mv P-values from 0.00003 to <0.05) but not with NSCD or NCD. When dichotomized PWRSD, PWR, PWRSD/SDNN, and PWR/SDNN were added to the clinical risk model for SCD/SCD, the C-index increased from 0.799 to 0.834 and integrated discrimination index and net reclassification index improved significantly (P < 0.001). CONCLUSION: Variability of P-morphology representing temporo-spatial heterogeneity of atrial depolarization, specifically when combined with cardiac autonomic regulation, independently predicts the risk of SCD in patients with CAD.

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1.

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 mm2, 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.