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.

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.

Risk factors for major adverse cardiovascular events after the first acute coronary syndrome.

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.

Early Growth Patterns and Cardiac Structure and Function at Midlife: Northern Finland 1966 Birth Cohort Study.

OBJECTIVES: To evaluate the influence of early growth patterns that have previously been associated with later cardiometabolic risk on cardiac left ventricular (LV) structure and function in midlife. STUDY DESIGN: A subpopulation of the Northern Finland Birth Cohort 1966 took part in follow-up, including echocardiography (n = 1155) at the age of 46 years. Body mass index (BMI) growth curves were modeled based on frequent anthropometric measurements in childhood. Age and BMI at adiposity peak (n = 482, mean age 9.0 months) and at adiposity rebound (n = 586, mean age 5.8 years) were determined. Results are reported as unstandardized beta (ß) or OR with 95% CIs for 1 SD increase in early growth variable. RESULTS: Earlier adiposity rebound was associated with increased LV mass index (ß = -4.10 g/m2 (-6.9, -1.3); P = .004) and LV end-diastolic volume index (ß = -2.36 mL/m2 (-3.9, -0.84); P = .002) as well as with eccentric LV hypertrophy (OR 0.54 [0.38, 0.77]; P = .001) in adulthood in males. BMI at adiposity rebound was directly associated with LV mass index (ß = 2.33 g/m2 [0.80, 3.9]; P = .003). Higher BMI at both adiposity peak and at adiposity rebound were associated with greater LV end-diastolic volume index (ß = 1.47 mL/m2; [0.51, 2.4], ß = 1.28 mL/m2 [0.41, 2.2], respectively) and also with eccentric LV hypertrophy (OR 1.41 [1.10, 1.82], OR 1.53 [1.23, 1.91], respectively) and LV concentric remodeling (OR 1.38 [1.02, 1.87], OR 1.40 [1.06, 1.83], respectively) in adulthood (P < .05 for all). These relationships were only partly mediated by adult BMI. CONCLUSIONS: Early growth patterns in infancy and childhood contribute to cardiac structure at midlife.

Peptide hormones and risk for future cardiovascular events among prediabetics: a 20-year follow-up in the OPERA study.

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.

Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study.

BACKGROUND: A small proportion of patients undergoing primary prophylactic implantation of implantable cardioverter defibrillators (ICDs) experiences malignant arrhythmias. We postulated that periodic repolarisation dynamics, a novel marker of sympathetic-activity-associated repolarisation instability, could be used to identify electrically vulnerable patients who would benefit from prophylactic implantation of ICDs by way of a reduction in mortality. METHODS: We did a prespecified substudy of EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD), a prospective, investigator-initiated, non-randomised, controlled cohort study done at 44 centres in 15 EU countries. Patients aged 18 years or older with ischaemic or non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (≤35%) were eligible for inclusion if they met guideline-based criteria for primary prophylactic implantation of ICDs. Periodic repolarisation dynamics from 24-h Holter recordings were assessed blindly in patients the day before ICD implantation or on the day of study enrolment in patients who were conservatively managed. The primary endpoint was all-cause mortality. Propensity scoring and multivariable models were used to assess the interaction between periodic repolarisation dynamics and the treatment effect of ICDs on mortality. FINDINGS: Between May 12, 2014, and Sept 7, 2018, 1371 patients were enrolled in our study. 968 of these patients underwent ICD implantation, and 403 were treated conservatively. During follow-up (median 2·7 years [IQR 2·0-3·3] in the ICD group and 1·2 years [0·8-2·7] in the control group), 138 (14%) patients died in the ICD group and 64 (16%) patients died in the control group. We noted a 43% reduction in mortality in the ICD group compared with the control group (adjusted hazard ratio [HR] 0·57 [95% CI 0·41-0·79]; p=0·0008). Periodic repolarisation dynamics significantly predicted the treatment effect of ICDs on mortality (adjusted p=0·0307). The mortality benefits associated with ICD implantation were greater in patients with periodic repolarisation dynamics of 7·5 deg or higher (n=199; adjusted HR 0·25 [95% CI 0·13-0·47] for the ICD group vs the control group; p<0·0001) than in those with periodic repolarisation dynamics less than 7·5 deg (n=1166; adjusted HR 0·69 [95% CI 0·47-1·00]; p=0·0492; pinteraction=0·0056). The number needed to treat was 18·3 (95% CI 10·6-4895·3) in patients with periodic repolarisation dynamics less than 7·5 deg and 3·1 (2·6-4·8) in those with periodic repolarisation dynamics of 7·5 deg or higher. INTERPRETATION: Periodic repolarisation dynamics predict mortality reductions associated with prophylactic implantation of ICDs in contemporarily treated patients with ischaemic or non-ischaemic cardiomyopathy. Periodic repolarisation dynamics could help to guide treatment decisions about prophylactic ICD implantation. FUNDING: The European Community's 7th Framework Programme.

Prognostic significance of P-wave morphology in patients with coronary artery disease.

INTRODUCTION: The prognostic significance of P-wave morphology in patients with coronary artery disease (CAD) is not well-known. METHODS: A total of 1946 patients with angiographically verified CAD were included in the Innovation to reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study. The P-wave morphology could be analyzed in 1797 patients. RESULTS: During 7.4 ± 2.0 years, a total of 168 (9.3%) patients died or experienced resuscitation from sudden cardiac arrest (SCA), 43 (2.4%) patients experienced sudden cardiac death (SCD) or were resuscitated from SCA, 37 (2.1%) patients succumbed to non-SCD (NSCD), and 88 (4.9%) patients to noncardiac death (NCD). Of the P-wave parameters, the absolute P-wave residuum (PWR), the heterogeneity of the P-wave morphology (PWH), and the P-wave duration (Pdur) had the closest univariate association with the risk of SCD/SCA (0.0038 ± 0.0026 vs 0.0022 ± 0.0017, P < .001; 11.0 ± 5.2 vs 8.6 ± 3.6, P < .01; 142.7 ± 16.9 vs 134.8 ± 14.3 milliseconds, P < .01; SCD/SCA vs no SCD/SCA, respectively). After adjustments with factors that were associated with the risk of SCD/SCA, such as diabetes, smoking, left bundle branch block, high-sensitivity C-reactive protein, and high-sensitivity troponin T, PWR (P < .001), PWH (P < .05), and Pdur (P < 0.01) still predicted SCD/SCA but not non-sudden cardiac death. When these parameters were added to the SCD/SCA clinical risk model, the discrimination and reclassification accuracy of the risk model increased significantly (P < .05, P < .001) and the C-index increased from 0.745 to 0.787. CONCLUSION: The P-wave morphology parameters independently predict SCD/SCA in patients with CAD.

Musculoskeletal pains and cardiovascular autonomic function in the general Northern Finnish population.

BACKGROUND: Heart rate variability (HRV) and baroreflex sensitivity (BRS) measurements provide means for the objective assessment of cardiovascular autonomic function. As previous studies have associated chronic pain with abnormal autonomic function, we aimed to characterize the relationship between the number of musculoskeletal pain sites (NPS), pain intensity, and cardiovascular autonomic function among the population-based Northern Finland Birth Cohort 1966. METHODS: At the age of 46, cohort members self-reported their musculoskeletal pains (enabling the determination of NPS [0-8] and pain intensity [Numerical Rating Scale, NRS, 0-10]) and underwent clinical assessments of cardiovascular autonomic function in seated and standing positions (HRV variables: heart rate [HR] and root mean square of successive differences in beat-to-beat intervals [rMSSD] for the entire cohort; BRS variables: low-frequency systolic blood pressure variability [SBPV] and cross-spectral baroreflex sensitivity [BRS] for those attending the examination in Oulu, Finland). Extensive confounder data were also collected (body mass index, physical activity, smoking, Hopkins Symptom Checklist-25, comorbidities, and medications). The full samples included 4186 and 2031 individuals (HRV and BRS samples, respectively). Three subanalyses focused on individuals with intense and frequent pain, individuals with symptoms of depression and anxiety, and the relationship between pain intensity and autonomic parameters. RESULTS: Linear regression models showed varying associations between NPS, pain intensity, and cardiovascular autonomic parameters. However, after all adjustments NPS was only associated with one outcome among women (BRS, standing: beta = - 0.015, p = 0.048) and two among men (HR, seated: beta = - 0.902, p = 0.003; HR, standing: beta = - 0.843, p = 0.014). Pain intensity was not associated with any outcome after full adjustments. Significant sex*pain interactions were found in the data. CONCLUSIONS: Our data suggest that musculoskeletal pain has, at most, a limited independent association with cardiovascular autonomic function. Future studies should carefully account for the potential confounders and sex interactions that this study revealed.

Self-Reported Polycystic Ovary Syndrome Is Associated With Hypertension: A Northern Finland Birth Cohort 1966 Study.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with many traditional cardiovascular disease risk factors, but it is unclear whether PCOS is an independent risk factor for hypertension. OBJECTIVE: To investigate in a population-based setup whether PCOS associates with the risk of hypertension independently of body mass index (BMI) and with cardiovascular manifestations. DESIGN: Cross-sectional assessments in the Northern Finland Birth Cohort 1966 at ages 31 and 46 years. SETTING: General community. PARTICIPANTS: Women who reported both oligo/amenorrhea and hirsutism at age 31 years and/or a diagnosis of PCOS by age 46 years [self-reported PCOS (srPCOS), n = 279] and women without PCOS symptoms or diagnosis (n = 1577). INTERVENTION: None. MAIN OUTCOME MEASURES: Blood pressure (BP), BMI, and cardiovascular manifestations. RESULTS: Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31 years, women with srPCOS had significantly higher systolic BP (SBP) and diastolic BP (DBP) than control women (SBP: normal weight: 119.9 ± 13.2 vs 116.9 ± 11.4 mm Hg, P = 0.017; overweight/obese: 126.1 ± 14.3 vs 123.0 ± 11.9 mm Hg, P = 0.031; and DBP: normal weight: 75.5 ± 10.0 vs 72.4 ± 9.6 mm Hg, P = 0.003; overweight/obese: 80.7 ± 11.8 vs 78.0 ± 10.6 mm Hg, P = 0.031). At age 46 years, srPCOS was significantly associated with hypertension (adjusted odds ratio = 1.56; 95% CI, 1.14 to 2.13) independently of BMI and with higher cardiovascular morbidity (6.8% vs 3.4%, P = 0.011). Hypertensive srPCOS displayed consistent, unfavorable changes in cardiac structure and function compared with controls. CONCLUSION: Women with srPCOS displayed higher BP compared with controls already at early age and srPCOS was associated with hypertension independently of overweight/obesity. srPCOS was associated with increased cardiovascular morbidity in premenopausal women, suggesting that cardiovascular disease risk factors should be screened and efficiently managed early enough in women with PCOS.

Dietary sodium intake is associated with long-term risk of new-onset atrial fibrillation.

BACKGROUND: The association between dietary salt intake and hypertension has been well documented. We evaluated the association between dietary sodium intake and the incidence of new-onset atrial fibrillation (AF) during a mean follow-up of 19 years among 716 subjects from the Oulu Project Elucidating Risk of Atherosclerosis (OPERA) cohort. MATERIAL AND METHODS: Dietary sodium intake was evaluated from a seven-day food record. The diagnosis of AF (atrial flutter included) was made if ICD-10 code I48 was listed in the hospital discharge records during follow-up. RESULTS: In the Kaplan-Meier curves, when quartiles of sodium consumption were considered, the cumulative proportional probabilities for AF events were higher in the highest (4th) quartile (16.8%) than in the lower quartiles (1st 6.7%, 2nd 7.3% and 3rd 10.6%) (p = .003). In the Cox regression analysis, sodium consumption (g/1000 kcal) as a continuous variable was independently associated with AF events (Hazard Ratio = 2.1 (95% CI, 1.2 to 3.7) p =.015) when age, body mass index, smoking (pack-years), office systolic blood pressure, left atrium diameter, left ventricular mass index and the use of any antihypertensive therapy were added as covariates. CONCLUSIONS: These findings indicate that sodium intake is associated with the long-term risk of new-onset AF. Further confirmatory studies are needed. Key messages Sodium consumption correlated positively with CV risk factors: age, smoking, SBP, BMI and LDL-cholesterol. When quartiles of sodium consumption were considered, the AF incidence was higher in the highest quartile compared to lower quartiles. Sodium consumption as a continuous variable was independently associated with AF events when age, BMI, smoking, SBP, LAD, LVMI and the use of any antihypertensive therapy were considered.

Cancer increases the risk of atrial fibrillation during long-term follow-up (OPERA study).

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.

Biomarkers as predictors of sudden cardiac death in coronary artery disease patients with preserved left ventricular function (ARTEMIS study).

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.

Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders.

BACKGROUND: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. METHODS: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. RESULTS: Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. CONCLUSIONS: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.

Inferolateral early repolarization among non-ischaemic sudden cardiac death victims.

Aim: Inferolateral early repolarization (ER) has been associated with an increased risk of sudden cardiac death (SCD). However, this association is thought to be mainly due to ischaemic SCD. The association of ER and non-ischaemic SCD has not been studied. The aim was to evaluate whether inferolateral ER is associated with non-ischaemic SCD. Methods and results: Study population consists of 275 consecutive victims of non-ischaemic SCD with 12-lead ECG and control group of general population cohort with 10 864 subjects. Sudden cardiac deaths were verified as non-ischaemic by medicolegal autopsy. Hypertensive cardiomyopathy (HTCMP) (25%), alcohol related dilated cardiomyopathy (ACMP) (24%), obesity associated cardiomyopathy (OCMP) (23%), and idiopathic myocardial fibrosis (IMF) (15%) were the most common causes of non-ischaemic SCD. A structurally normal heart was seen in only 1.5%. The prevalence of inferolateral ER was 20.7% among patients with non-ischaemic SCD compared to 5.3% in the general population (P < 0.001). The ECG pattern was accompanied with a horizontal/descending ST segment in 95% of the cases. The prevalence of inferolateral ER was slightly higher in the HTCMP group (26%) and the ACMP group (24%) than in the IMF group (20%) and the OCMP group (13%). The history of previously diagnosed cardiac diseases was not higher among subjects with ER (55%) than those without (59%, P = 0.59). Conclusion: The prevalence of inferolateral ER among non-ischaemic SCD victims is high. Almost all ER patterns are accompanied with the malignant horizontal/descending ST segment morphology suggesting that inferolateral ER is not only associated with an ischaemic SCD but also a non-ischaemic SCD.

Effect of Changes in Physical Activity on Risk for Cardiac Death in Patients With Coronary Artery Disease.

Leisure-time physical activity (LTPA) is associated with longevity in patients with coronary artery disease (CAD). However, less is known about prognostic significance of longitudinally assessed LTPA in patients with stable CAD. The present study assessed the relationship between changes in LTPA and cardiac mortality in patients with CAD. Patients with angiographically documented CAD (n = 1,746) underwent clinical examination and echocardiography at the baseline. Lifestyle factors, including LTPA (inactive, irregularly active, active, highly active), were surveyed at baseline and after 2 years' follow-up. Thereafter, the patients entered the follow-up (median: 4.5 years; first to third quartile: 3.4 to 5.8 years) during which cardiac deaths were registered (n = 68, 3.9%). The patients who remained inactive (n = 114, 18 events, 16%) and became inactive (n = 228, 18 events, 8%) had 7.6- (95% confidence interval [CI] 4.2 to 13.6) and 3.7-fold (95% CI 2.1 to 6.7) univariate risk for cardiac death compared with those who remained at least irregularly active (n = 1,351, 30 events, 2%), respectively. After adjustment for age, gender, body mass index, diabetes, previous myocardial infarction, left ventricular ejection fraction, angina pectoris grading, cardiovascular event during initial 2-year follow-up, smoking and alcohol consumption, the patients who remained inactive and became inactive still had 4.9- (95% CI 2.4 to 9.8, p <0.001) and 2.4-fold (95% CI 1.3 to 4.5, p <0.01) risk for cardiac death, respectively, compared with patients remaining at least irregularly active. In conclusion, LTPA has important prognostic value for cardiac death in patients with stable CAD. Even minor changes in LTPA over 2 years were related to the subsequent risk for cardiac death.

Tracking interlead heterogeneity of R- and T-wave morphology to disclose latent risk for sudden cardiac death.

Sudden cardiac death (SCD) due primarily to ventricular fibrillation claims 1.5 million lives worldwide each year. In 45%-50% of cases, it is the first manifestation of underlying heart disease. Traditional risk factors including smoking, hypertension, age, sex, as well as depressed left ventricular ejection fraction lack sufficient sensitivity and specificity to forewarn of impending life-threatening arrhythmias. There has been a decades-long search for electrocardiographic (ECG) markers of SCD risk. Several interval-based indices such as QT dispersion and Tpeak-Tend interval held initial promise but ultimately yielded mixed results. Recently, the focus has been on interlead heterogeneity of R- and T-wave morphology. The new approaches have involved advanced analytical tools including vectorcardiographic techniques and second central moment analysis of QRS-aligned templates to quantify heterogeneity of depolarization and repolarization waveforms. The results of current studies appear to be robust and worthy of further exploration. This review examines the electrophysiological underpinnings of heterogeneity-based risk assessment and provides an update of clinical techniques. We also discuss future directions whereby tracking heterogeneity may help to disclose latent risk for SCD not only in ECG recordings made at rest but also during ambulatory ECG monitoring and exercise tolerance testing.

Ambulatory Blood Pressure Characteristics and Long-Term Risk for Atrial Fibrillation.

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.

Association between Birth Characteristics and Cardiovascular Autonomic Function at Mid-Life.

BACKGROUND: Low birth weight is associated with an increased risk of cardiovascular diseases in adulthood. As abnormal cardiac autonomic function is a common feature in cardiovascular diseases, we tested the hypothesis that low birth weight may also be associated with poorer cardiac autonomic function in middle-aged subjects. METHODS: At the age of 46, the subjects of the Northern Finland Birth Cohort 1966 were invited to examinations including questionnaires about health status and life style and measurement of vagally-mediated heart rate variability (rMSSD) from R-R intervals (RRi) and spontaneous baroreflex sensitivity (BRS) in both seated and standing positions. Maternal parameters had been collected in 1965-1966 since the 16th gestational week and birth variables immediately after delivery. For rMSSD, 1,799 men and 2,279 women without cardiorespiratory diseases and diabetes were included and 902 men and 1,020 women for BRS. The analyses were adjusted for maternal (age, anthropometry, socioeconomics, parity, gestational smoking) and adult variables (life style, anthropometry, blood pressure, glycemic and lipid status) potentially confounding the relationship between birth weight and autonomic function. RESULTS: In men, birth weight correlated negatively with seated (r = -0.058, p = 0.014) and standing rMSSD (r = -0.090, p<0.001), as well as with standing BRS (r = -0.092, p = 0.006). These observations were verified using relevant birth weight categories (<2,500 g; 2,500-3,999 g; ≥4,000 g). In women, birth weight was positively correlated with seated BRS (r = 0.081, p = 0.010), but none of the other measures of cardiovascular autonomic function. These correlations remained significant after adjustment for potential confounders (p<0.05 for all). CONCLUSIONS: In men, higher birth weight was independently associated with poorer cardiac autonomic function at mid-life. Same association was not observed in women. Our findings suggest that higher, not lower, birth weight in males may contribute to less favourable cardiovascular autonomic regulation and potentially to an elevated cardiovascular risk in later life.

12-Lead electrocardiogram as a predictor of sudden cardiac death: from epidemiology to clinical practice.

Sudden cardiac death (SCD) causes a high burden of premature deaths in the population affecting subjects of all ages. The identification of subjects at high risk for SCD is of great importance as the prevention of many of these events would be possible with the treatment of underlying cardiac diseases and the use of implantable cardioverter-defibrillators (ICD). However, the current selection of patients for ICD therapy is based solely on left ventricular ejection fraction, and thus a substantial portion of patients at high risk does not qualify for the therapy. Role of the standard electrocardiogram (ECG) in SCD risk stratification has been under active research during the last decade and multiple abnormalities of depolarization and repolarization on the ECG associated with an increased risk of SCD have been identified. In this review, we describe the basic pathophysiological principles behind these changes. We also review the current knowledge of the prognostic significance of ECG predictors of SCD in the general population, and in patients with coronary heart disease (CHD), heart failure, cardiomyopathies, and in inheritable arrhythmia syndromes. Also, insights into the novel digital ECG signal processing techniques are provided.