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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, b

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.

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.

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.

Cardiovascular diseases are the leading cause of death in Finland. Coronary heart disease is the main group of cardiovascular diseases and 22,000 people are hospitalized in Finland every year because of acute coronary syndrome. The risk factors and long-term prognosis of coronary heart disease should be studied to assess the impact coronary heart disease has on public economy and on the health of the population. In the first publication of this thesis, the long-term prognosis of acute coronary syndrome was studied between the years 1993–2012. The study population was drawn from the FINAMI register and it included patients who had survived 28 days after their first ever acute coronary syndrome event. The results were then compared to a healthy population drawn from the FINRISK population surveys of the same areas and of the same age as the FINAMI study patients. In the third publication of this thesis, risk factors for recurrent events after the first acute coronary syndrome event were evaluated. The purpose of the second publication of this thesis was to study the validity of ST-elevation myocardial infarction and non-ST-elevation myocardial infarction diagnoses in the Finnish hospital discharge register. The results showed that even though the prognosis of acute coronary syndrome had improved during the years 1993–2012 it was still worse than the prognosis of a general population sample drawn from the FINRISK participants. Almost 25% of the first acute coronary syndrome survivors had a recurrent event within the first year after the primary event and 37% had a recurrence within three years. Especially diabetes and heart failure during the index event were risk factors for a recurrence. The subtypes of acute coronary syndrome (ST-elevation myocardial infarction and non-ST-elevation myocardial infarction) could not be used in scientific research as such because the validity of these diagnoses in the Finnish hospital discharge register was poor. It is extreme, Tiivistelmä Verenkiertoelinsairaudet aiheuttavat eniten kuolemia Suomessa vuositasolla. Sepelvaltimotauti on Suomessa merkittävin verenkiertoelinsairauksien ryhmä ja akuutin sepelvaltimotaudin vuoksi Suomessa sairaalaan joutuu vuosittain 22 000 ihmistä. Ottaen huomioon millaisen kansantaloudellisen kuorman sepelvaltimotauti aiheuttaa on perusteltua tutkia sen pitkäaikaisennusteen ja riskitekijöiden muutoksia väestössä. Tämän väitöskirjan ensimmäisen osajulkaisun tarkoitus oli tutkia akuutin sepelvaltimo-oireyhtymän pitkäaikaisennustetta vuosien 1993 ja 2012 välillä. Aineisto koostui ensimmäisen akuutin sepelvaltimo-oireyhtymän sairastaneista FINAMI-rekisteripotilaista. Tuloksia verrattiin terveeseen verrokkiryhmään, joka saatiin FINRISK-aineistosta. FINRISK- ja FINAMI-aineistot oli kerätty samoilta asuinalueilta ja niiden ikärakenteet olivat samanlaisia. Toisessa osajulkaisussa perehdyimme sydäninfarktin alaryhmien eli ST-nousuinfarktin ja sydäninfarktin ilman ST-nousuja paikkansapitävyyteen hoitoilmoitusjärjestelmässä. Kolmannessa osajulkaisussa tutkimme näiden ensimmäisen akuutin sepelvaltimo-oireyhtymän sairastaneiden potilaiden riskitekijöitä, jotka altistavat heidät uusintakohtauksille. Tuloksista kävi ilmi, että akuutin sepelvaltimo-oireyhtymän ennuste oli parantunut seurantajakson aikana, mutta oli edelleen selkeästi tervettä väestöä heikompi. Lähes 25 % potilaista sai uusintakohtauksen ensimmäisen vuoden aikana ja kolmen vuoden kohdalla 37 % oli saanut uusintakohtauksen. Erityisesti diabetes ja sydämen vajaatoiminta ensimmäisen kohtauksen aikana olivat merkittäviä riskitekijöitä uusintakohtauksille. Sydäninfarktin tyyppiä (ST-nousuinfarkti tai sydäninfarkti ilman ST-nousuja) ei voitu käyttää tutkimuksessa, koska hoitoilmoitusjärjestelmään merkityt ICD-koodatut diagnoosit eivät pitäneet riittävästi paikkaansa, jotta niitä olisi voitu käyttää tieteellisessä tutkimuksessa. Etenkin nyt, suurten terveydenhuollon muutosten aikana, olisi tärkeää saada tutkittua tie

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.

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.

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.

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 lon

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.

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.

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: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. Methods: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. Findings: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square m

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.

Cardiovascular (CV) diseases are the number one cause of mortality worldwide, causing nearly 19 million deaths in 2019. Estimating the individual CV risk is essential for targeting the preventative interventions more effectively. Currently, international guidelines recommend using standardized risk calculators for estimating the patient’s future risk of a CV event. In “borderline” risk individuals, these guidelines further recommend using additional clinical tests, such as coronary artery calcium score, for refining the risk estimation and guiding the clinical treatment decisions. Relatively little is known about much simpler and safer clinical tests in CV risk assessment. The aim of the current study was to explore whether plasma resistin concentration, carotid or femoral bruits, or ultrasonographically assessed carotid intima-media thickness (IMT) and abdominal aorta plaques could provide additional prognostic information beyond traditional CV risk factors in individual risk assessment. The study population consisted of middle-aged and elderly Finnish subjects participating in the Oulu Project Elucidating Risk of Atherosclerosis (OPERA) project. Our results show that increasing plasma resistin concentration is associated with significantly increased risk of all-cause mortality in elderly Finnish participants. Similarly, our results show that an audible bruit from either carotid or femoral arteries is a strong predictor of fatal CV events in a middle-aged population. Ultrasonographically assessed carotid IMT is a controversial surrogate marker of subclinical atherosclerosis, and our results indicate that it does not predict CV events after adjusting for other CV risk factors. On the other hand, our results show that ultrasonographically measured abdominal aorta plaque length is a strong predictor of future CV events and provides prognostic information in addition to traditional CV risk factors during a follow-up period of over 20 years. In conclusion, this, Tiivistelmä Sydän- ja verisuonisairaudet (SV) ovat maailman yleisin kuolleisuuden syy aiheuttaen lähes 19 miljoonaa kuolemaa vuonna 2019. Yksilöllinen SV-sairauksien riskinarvio on ensiarvoisen tärkeää ennaltaehkäisevien toimenpiteiden tehokkaassa kohdentamisessa. Kansainväliset suositukset suosittelevat riskilaskureiden käyttöä potilaan tulevan SV-tapahtuman riskinarviossa. Samat suositukset kehottavat käyttämään tarkentavia kliinisiä tutkimuksia, kuten sepelvaltimoiden kalsifikaatioiden pisteytystä, riskinarvion ja kliinisten hoitopäätösten tukena yksilöillä, joiden SV-tapahtuman riski on ”rajaviivalla”. Verrattain vähän tiedetään paljon yksinkertaisemmista kliinisistä testeistä SV-tapahtumien riskinarviossa. Tämän tutkimuksen tarkoitus oli selvittää tuovatko plasman resistiinipitoisuus, kaula- tai reisivaltimosta kuullut suhinat tai ultraäänellä määritetty kaulavaltimon intima-media paksuus (IMT) ja vatsa-aortan plakkien pituus prognostista informaatiota tavanomaisten SV-sairauksien riskitekijöiden lisäksi yksilöllisessä riskinarviossa. Tutkimuksen aineisto koostuu keski-ikäisistä ja iäkkäistä suomalaisista, jotka osallistuivat Oulu Project Elucidating Risk of Atherosclerosis (OPERA) -projektiin. Tuloksemme osoittavat, että kohonnut plasman resistiinipitoisuus on yhteydessä merkittävästi kohonneeseen kuolleisuuteen iäkkäillä henkilöillä. Vastaavasti tuloksemme osoittavat, että joko kaula- tai reisivaltimosta auskultoiden kuultu suhina on voimakas fataalien SV-tapahtumien ennustaja keski-ikäisillä henkilöillä. Ultraäänellä määritetty kaulavaltimon IMT on kiistanalainen subkliinisen ateroskleroosin mitta, ja tuloksemme näyttivät, ettei se ennustanut tulevia SV-tapahtumia, kun riskimalli vakioitiin tavanomaisilla riskitekijöillä. Sen sijaan tuloksemme näyttivät, että ultraäänellä määritetty vatsa-aortan plakkien pituus on voimakas tulevien SV-tapahtumien ennustaja ja plakkien pituus antaa prognostista informaatiota tavanomaisten SV-riskitekijöiden lisäksi yli 20 vuo

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.

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.

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.

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.

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 = 0.046)]. However, PNPLA3 rs738409 [1.049 (0.650–1.692, p =0 .844)], TM6SF2 rs58542926 [0.721 (0.369–1.411, p = 0.340)] or MBOAT7 rs641738 [0.885 (0.543–1.439, p = 0.621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p =0.013) 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.

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: Fragmented QRS (fQRS) on 12-lead electrocardiogram (ECG) is associated with scarred myocardium and adverse outcome. However, the data on gender differences in terms of its prevalence and prognostic value is sparse. The aim of this study was to evaluate whether gender differences in fQRS exist among subjects drawn from populations with different risk profiles. Methods: We analyzed fQRS from 12-lead ECG in 953 autopsy-confirmed victims of sudden cardiac death (SCD) (78% men; 67.0 ± 11.4 yrs), 1900 coronary artery disease (CAD) patients with angiographically confirmed stenosis of ≥50% (70% men; 66.6 ± 9.0 yrs, 43% with previous myocardial infarction [MI]), and in 10,904 adults drawn from the Finnish adult general population (52% men; 44.0 ± 8.5 yrs). Results: Prevalence of fQRS was associated with older age, male sex and the history and severity of prior cardiac disease of subjects. Among the general population fQRS was more commonly found among men in comparison to women (20.5% vs. 14.8%, p < 0.001). The prevalence of fQRS rose gradually along with the severity of prior cardiac disease in both genders, yet remained significantly higher in the male population: subjects with suspected or known cardiac disease (25.4% vs. 15.8% p < 0.001), CAD patients without prior MI (39.9% vs. 26.4%, p < 0.001), CAD patients with prior MI (42.9% vs. 31.2%, p < 0.001), and victims of SCD (56.4% vs. 44.4%, p < 0.001). Conclusions: The prevalence of QRS fragmentation varies in different populations. The fragmentation is clearly related to the underlying cardiac disease in both genders, however women seem to have significantly lower prevalence of fQRS in each patient population in comparison to men.