Showing papers by "Maja-Lisa Løchen published in 2017"

Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Abstract: Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

European Heart Rhythm Association (EHRA)/European Association of Cardiovascular Prevention and Rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (APHRS)

Abstract: ACEI, : angiotensin converting enzyme inhibitors AF, : atrial fibrillation ARB, : angiotensin receptor blockers AVNRT, : atrioventricular nodal re-entry tachycardia BMI, : body mass index CHADS2, : cardiac failure, hypertension, age, diabetes, stroke (doubled) CHA2DS2-VASc, : congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 (doubled), diabetes, stroke/transient ischaemic attack (doubled)-vascular disease, age 65–74, sex category (female) CI, : confidence interval FU, : follow-up HR, : hazard ratio HDL, : high-density lipoprotein cholesterol ICD, : implantable cardioverter defibrillators LA, : left atrium LDL, : low-density lipoprotein cholesterol LV, : left ventricle NOAC, : non-VKA oral anticoagulant OAC, : oral anticoagulation OR, : odds ratio OSA, : obstructive sleep apnoea n 3-PUFA, : ω-3 polyunsaturated fatty acids RAAS, : renin–angiotensin–aldosterone system RR, : relative risk SBP, : systolic blood pressure SAMe-TT2R2, : sex (female), age (<60 years), medical history, treatment (interacting drugs, eg amiodarone for rhythm control), tobacco use (within 2 years) (doubled), Race (non-Caucasian) (doubled) SVT, : supraventricular tachyarrhythmia VKA, : vitamin K antagonist Atrial fibrillation (AF) is an important and highly prevalent arrhythmia, which is associated with significantly increased morbidity and mortality, including a four- to five-fold increased risk for stroke,1,2 a two-fold increased risk for dementia,3,4 a three-fold risk for heart failure,2 a two-fold increased risk for myocardial infarction,5,6 and a 40–90% increased risk for overall mortality2,7 The constantly increasing number of AF patients and recognition of increased morbidity, mortality, impaired quality of life, safety issues, and side effects of rhythm control strategies with antiarrhythmic drugs, and high healthcare costs associated with AF have spurred numerous investigations to develop more effective treatments for AF and its complications8 Although AF treatment has been studied extensively, AF prevention has received relatively little attention, while it has paramount importance in the prevention of morbidity and mortality, and complications associated with arrhythmia and its treatment Current evidence shows a clear association between the presence of modifiable risk factors and the risk of developing AF By implementing AF risk reduction strategies aiming at risk factors such as obesity, hypertension, diabetes, and obstructive sleep apnoea (OSA), which are interrelated, we impact upon the escalating …

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation.

Abstract: Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.

Declining Incidence of Ischemic Stroke: What Is the Impact of Changing Risk Factors? The Tromsø Study 1995 to 2012

Abstract: Background and Purpose— It is proposed that 20% to 40% of the decline in first-ever stroke incidence is attributed to the improvement of risk factor control. We estimated the impact of modifiable cardiovascular risk factors on the changing incidence of ischemic stroke (IS) between 1995 and 2012, using individual person data from repeated surveys in a general population. Methods— The proportion of the IS incidence decline explained by change in each risk factor over time was estimated from 1995 to 2012 by Poisson regression among 26 329 participants who attended the fourth Tromso survey in 1994 to 1995. Hazard ratios for IS were estimated with Cox proportional hazards regression among 27 936 participants who attended at least 1 of the Tromso surveys in 1994 to 1995, 2001, or 2007 to 2008. Age- and sex-adjusted means or prevalences of risk factors over time were estimated by generalized estimating equations. Results— There were 1226 first-ever IS during 367 636 person-years of follow-up. Changes in cardiovascular risk factors accounted for 57% of the decrease in IS incidence from 1995 to 2012. The most important contributors were decreasing mean systolic blood pressure and smoking prevalence, accounting for 26% and 17% of the observed decline, respectively. Conversely, increasing diabetes mellitus prevalence contributed negatively to the declining IS incidence. Conclusions— Changes in cardiovascular risk factors explained 57% of the decrease in IS incidence from 1995 to 2012. Reduction in systolic blood pressure and prevalence of smoking were the most important contributors.

European Heart Rhythm Association (EHRA)/European Association of Cardiovascular Prevention and Rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (APHRS).

Abstract: Atrial fibrillation (AF) is an important and highly prevalent arrhythmia, which is associated with significantly increased morbidity and mortality, including a four- to five-fold increased risk for stroke,1,2 a two-fold increased risk for dementia,3,4 a three-fold risk for heart failure,2 a two-fold increased risk for myocardial infarction,5,6 and a 40–90% increased risk for overall mortality.2,7 The constantly increasing number of AF patients and recognition of increased morbidity, mortality, impaired quality of life, safety issues, and side effects of rhythm control strategies with antiarrhythmic drugs, and high healthcare costs associated with AF have spurred numerous investigations to develop more effective treatments for AF and its complications.8 Although AF treatment has been studied extensively, AF prevention has received relatively little attention, while it has paramount importance in the prevention of morbidity and mortality, and complications associated with arrhythmia and its treatment. Current evidence shows a clear association between the presence of modifiable risk factors and the risk of developing AF. By implementing AF risk reduction strategies aiming at risk factors such as obesity, hypertension, diabetes, and obstructive sleep ap-noea (OSA), which are interrelated, we impact upon the escalating incidence of AF in the population and ultimately decrease the healthcare burden of associated co-morbidities of AF. To address this issue, a Task Force was convened by the European Heart Rhythm Association and the European Association of Cardiovascular Prevention and Rehabilitation, endorsed by the Heart Rhythm Society and Asia-Pacific Heart Rhythm Society, with the remit to comprehensively review the published evidence available, to publish a joint consensus document on the prevention of AF, and to provide up-to-date consensus recommendations for use in clinical practice. In this document, our aim is to summarize the current evidence on the association of each modifiable risk factor with AF and the available data on the impact of possible interventions directed at these factors in preventing or reducing the burden of AF. While the evidence on AF prevention is still emerging, the topic is not fully covered in current guidelines and some aspects are still controversial. Therefore, there is a need to provide expert recommendations for professionals participating in the care of at-risk patients and populations, with respect to addressing risk factors and lifestyle modifications. Health economic considerations Atrial fibrillation is a costly disease, both in terms of direct, and indirect costs, the former being reported by cost of illness studies as per-patient annual costs in the range of US $2000–14200 in North America and of €450–3000 in Europe.9 In individuals with AF or at risk of developing AF, any effective preventive measure, intervention on modifiable risk factors or comorbidities, as well as any effective pharmacological or non-pharmacological treatment has the aim to reduce AF occurrence, thromboembolic events and stroke, morbidity and, possibly, mortality related to this arrhythmia. Apart from the clinical endpoints, achievement of these goals has economic significance, in terms of positive impact on direct and indirect costs and favourable cost–effectiveness at mid- or long-term, in the perspective of healthcare systems.10–12 In view of the epidemiological profile of AF and progressive aging of the population,13 an impressive increase of patients at risk of AF or affected by AF,14 also in an asymptomatic stage, is expected in the next decades, inducing a growing financial burden on healthcare systems, not only in Europe and North America, but also worldwide.15,16 In consideration of this emerging epidemiological threat due to AF, it is worth considering a paradigm shift, going beyond the conventional approach of primary prevention based on treatment of AF risk factors, but, instead, considering the potential for ‘primordial’ prevention, defined as prevention of the development of risk factors predisposing to AF in the first place.17 This approach, aimed at avoiding the emergence and penetration of risk factors into the population, has been proposed in general terms for the prevention of cardiovascular diseases17 and should imply combined efforts of policymakers, regulatory and social service agencies, providers, physicians, community leaders, and consumers, in an attempt to improve social and environmental conditions, as well as individual behaviours, in the pursuit of adopting healthy lifestyle choices.16 Since a substantial proportion of incident AF events can be attributable to elevated or borderline levels of risk factors for AF,18 this approach could be an effective way to reduce the financial burden linked to AF epidemiology. In terms of individual behaviour and adoption of a ‘healthy lifestyle’, it is worth considering that availability of full healthcare coverage (through health insurance or the healthcare system) may in some cases facilitate the unwanted risk of reducing, at an individual level, the motivation to adopt all the preventive measures that are advisable, in line with the complex concept of ‘moral hazard effect’.19 Patient education and patient empowerment are the correct strategies for avoiding this undesirable effect.

Longitudinal and secular trends in total cholesterol levels and impact of lipid-lowering drug use among Norwegian women and men born in 1905–1977 in the population-based Tromsø Study 1979–2016

Abstract: Objectives Elevated blood cholesterol is a modifiable risk factor for cardiovascular disease. Cholesterol level surveillance is necessary to study population disease burden, consider priorities for prevention and intervention and understand the effect of diet, lifestyle and treatment. Previous studies show a cholesterol decline in recent decades but lack data to follow individuals born in different decades throughout life. Methods We investigated changes in age-specific and birth cohort-specific total cholesterol (TC) levels in 43 710 women and men born in 1905–1977 (aged 20–95 years at screening) in the population-based Tromso Study. Fifty-nine per cent of the participants had more than one and up to six repeated TC measurements during 1979–2016. Linear mixed models were used to test for time trends. Results Mean TC decreased during 1979–2016 in both women and men and in all age groups. The decrease in TC in age group 40–49 years was 1.2 mmol/L in women and 1.0 mmol/L in men. Both the 80th and the 20th percentile of the population TC distribution decreased in both sexes and all age groups. Longitudinal analysis showed that TC increased with age to a peak around middle age followed by a decrease. At any given age, TC significantly decreased with increase in year born. Lipid-lowering drug use was rare in 1994, increased thereafter, but was low ( Conclusions We found a substantial decrease in mean TC levels in the general population between 1979 and 2016 in all age groups. In birth cohorts, TC increased with age to a peak around middle age followed by a decrease.

Myocardial infarction and future risk of cancer in the general population—the Tromsø Study

Abstract: The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n = 28,763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariable-adjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21–1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29–3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27–2.03) higher HR of future cancer more than 3 years after the event. The increased IRs were higher in women than men. Patients with MI had a higher short- and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.

Resting heart rate trajectories and myocardial infarction, atrial fibrillation, ischaemic stroke and death in the general population: The Tromsø Study.

Abstract: Background Resting heart rate is an established risk factor for cardiovascular disease, but long-term individual resting heart rate trajectories and their effect on cardiovascular disease morbidity and mortality have not yet been described. Methods This large population-based longitudinal study included 14,208 men and women aged 20 years or older, not pregnant and not using blood pressure medications, who attended at least two of the three Tromso Study surveys conducted between 1986-2001. Resting heart rate was measured using an automated Dinamap device. Participants were followed up from 2001 to 2012 with respect to myocardial infarction, atrial fibrillation, ischaemic stroke, cardiovascular disease death and total death. The Proc Traj statistical procedure was used to identify resting heart rate trajectories. Results Five common long-term resting heart rate trajectories were identified: low, moderate, decreasing, increasing and elevated. In men, an elevated resting heart rate trajectory was independently associated with an increased risk of myocardial infarction when low resting heart rate trajectory was used as a reference (hazard ratio 1.83, 95% confidence interval 1.11-3.02). Risk of total death in men was lowest in the low resting heart rate trajectory group and highest in the increasing and elevated resting heart rate trajectory groups. In women, the association between resting heart rate trajectories and myocardial infarction was similar to that in men, but it was not significant. Conclusions Among the five long-term resting heart rate trajectories we identified, increasing and elevated trajectories were associated with an increased risk of myocardial infarction and total death in men. Our results suggest that changes in long-term individual resting heart rate in the general population may provide additional prognostic information.

Association of occasional smoking with total mortality in the population-based Tromsø study, 2001-2015.

Abstract: Objectives There is a shift in the smoking population from daily smokers to light or occasional smokers. The knowledge about possible adverse health effects of this new smoking pattern is limited. We investigated smoking habits with focus on occasional smoking in relation to total mortality in a follow-up study of a Norwegian general population. Setting A population study in Tromso, Norway. Methods We collected smoking habits and relevant risk factors in 4020 women and 3033 men aged 30–89 years in the Tromso Study in 2001. The subjects were followed up regarding total mortality through June 2015. Results Among the participants, there were 7% occasional smokers. Occasional smokers were younger, more educated and used alcohol more frequently than other participants. A total of 766 women and 882 men died during the follow-up. After the adjustment for confounders, we found that occasional smoking significantly increased mortality by 38% (95% CI 8% to 76%) compared with never smokers. We report a dose–response relationship in the hazards of smoking (daily, occasional, former and never smoking). Conclusions Occasional smoking is not a safe smoking alternative. There is a need for information to the general public and health workers about the health hazards of occasional smoking. More work should be done to motivate this often well-educated group to quit smoking completely.

Uric acid predicts mortality and ischaemic stroke in subjects with diastolic dysfunction: the Tromsø Study 1994-2013.

Abstract: Aims To investigate whether serum uric acid predicts adverse outcomes in persons with indices of diastolic dysfunction in a general population. Methods and results We performed a prospective cohort study among 1460 women and 1480 men from 1994 to 2013. Endpoints were all-cause mortality, incident myocardial infarction, and incident ischaemic stroke. We stratified the analyses by echocardiographic markers of diastolic dysfunction, and uric acid was the independent variable of interest. Hazard ratios (HR) were estimated per 59 μmol/L increase in baseline uric acid. Multivariable adjusted Cox proportional hazards models showed that uric acid predicted all-cause mortality in subjects with E/A ratio 1.5 (HR 1.51, 95% CI 1.09-2.09, P for interaction between E/A ratio category and uric acid = 0.02). Elevated uric acid increased mortality risk in persons with E-wave deceleration time 220 ms (HR 1.46, 95% CI 1.01-2.12 and HR 1.13, 95% CI 1.02-1.26, respectively; P for interaction = 0.04). Furthermore, in participants with isovolumetric relaxation time ≤60 ms, mortality risk was higher with increasing uric acid (HR 4.98, 95% CI 2.02-12.26, P for interaction = 0.004). Finally, elevated uric acid predicted ischaemic stroke in subjects with severely enlarged left atria (HR 1.62, 95% CI 1.03-2.53, P for interaction = 0.047). Conclusions Increased uric acid was associated with higher all-cause mortality risk in subjects with echocardiographic indices of diastolic dysfunction, and with higher ischaemic stroke risk in persons with severely enlarged left atria.

Increase in Weight in All Birth Cohorts in a General Population

Abstract: Background: Obesity is a risk factor for a number of chronic diseases. Few longitudinal studies have examined changes in body mass index (BMI [calculated as weight in kilograms divided by the square of the height in meters]). Objective: To investigate the changes in mean BMI and the prevalence of obesity in a large cohort examined several times during a 20-year period. Methods: Mean BMI, the percentage of subjects with low BMI (,20 kg/m 2 ), and the percentage who were obese (BMI $30 kg/m 2 ) were determined in a large population of men and women who were examined up to 4 times during a 20-year period (1974-1994/1995). In a longitudinal design, we observed 3541 men who attended all 4 screenings (1974-1994/1995) and 4993 women who attended the last 3 screenings (1979/ 1980-1994/1995). Results: The age- (25-49 years) and sex-adjusted mean BMI increased 1 kg/m 2 in men from 1974 to 1994/1995 and 0.9 kg/m 2 in women from 1979/1980 to 1994/1995. In the last survey, subjects aged 25 to 85 years were included. In most age groups, the mean BMI exceeded 25 kg/m 2 and the prevalence of obesity was 10% or higher in men and women aged 45 years or older. In the longitudinal analysis, the mean BMI in men aged 20 to 49 years increased 2.0 kg/m 2 during 20 years of observation and increased 2.4 kg/m 2 in women aged 20 to 49 years during 15 years of observation. The increase in BMI was larger in younger men than in older men. Conclusions: Body mass index increased in every examined birth cohort (1925-1964) during the 15- to 20year observation period. Primary prevention of further increased body weight should be a priority. Arch Intern Med. 2001;161:466-472

Atrial fibrillation is associated with cognitive decline in stroke-free subjects: The Tromsø Study

Abstract: Submitted manuscript version. Published version available in European Journal of Neurology, 24: 1485–1492

The electronic cigarette, do we need to worry?

Abstract: There are few high-quality studies on the effects of electronic cigarettes (e-cigarettes) on the cardiovascular system and this is a topic of increasing debate within cardiology. The study by Moheimani and co-workers that was published in February 2017 in JAMA Cardiology adds some clarity to the debate that e-cigarettes are probably not harmless. The researchers found that ecigarette use was related to increased sympathetic activity and oxidative stress in habitual e-cigarette users.[1]

Mutations in RPL3L and MYZAP increase risk of atrial fibrillation

Abstract: We performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.