Cardiovascular events according to blood pressure thresholds recommended by ACC/AHA.

AIM: The latest guidelines from ACC/AHA define hypertension at systolic blood pressure (SBP) 130-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg in contrast to guidelines from ESC/ESH defining hypertension at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The aim was to determine whether the ACC/AHA definition of hypertension identifies persons at elevated risk for future cardiovascular outcome. METHODS: In a Danish prospective cardiovascular study, 19,721 white men and women aged 20-98 years were examined up to five occasions between 1976 and 2015. The population was followed until December 2018. The ACC/AHA definition of the BP levels were applied: Normal: SBP <120 mmHg and DBP <80 mmHg, Elevated: SBP 120-129 mmHg and DBP <80 mmHg, Stage 1: SBP 130-139 mmHg or DBP 80-89 mmHg, Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg. Absolute 10-year risk was calculated taking repeated examinations, covariates, and competing risk into account. RESULTS: For all outcomes, the 10-year risk in stage 1 hypertension did not differ significantly from risk in subjects with normal BP: The 10-year risk of cardiovascular events in stage 1 hypertension was 14.1% [95% CI 13.2;15.0] and did not differ significantly from the risk in normal BP at 12.8% [95% CI 11.1;14.5] (p = 0.19). The risk was highest in stage 2 hypertension 19.4% [95% CI 18.9;20.0] and differed significantly from normal BP, elevated BP, and stage 1 hypertension (p < 0.001). The 10-year risk of cardiovascular death was 6.6% [95% CI 5.9;7.4] in stage 1 hypertension and did not differ significantly from the risk in normal BP at 5.7% [95% CI 4.1;7.3] (p = 0.33). CONCLUSIONS: Stage 1 hypertension as defined by the ACC/AHA guidelines has the same risk for future cardiovascular events as normal BP. In contrast, the definition of hypertension as suggested by ESC/ESH identifies patients with elevated risk of cardiovascular events.

Until 2017, there was worldwide agreement on defining hypertension at systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg.In 2017, the American Cardiology Societies (ACC and AHA) lowered the threshold for defining hypertension at SBP 130-139 mmHg or DBP 80-89 mmHg.Lowering the threshold might make healthy persons sick if the thresholds do not identify persons at high risk.Unnecessary medical treatment is associated with high economic cost for the health care systems.We wanted to explore whether applying the American BP definition in a Scandinavian population identified persons with elevated risk for cardiovascular disease.As part of the Copenhagen City Heart study, 19,721 men and women aged 20-98 years were followed from 1976.They went through up to five examinations between 1976 and 2018 including BP measurements.We applied the American BP thresholds and followed the persons until death or 2018.In Denmark all citizens have a unique identification number which is linked to all health care contacts and administrative registers.We used advanced statistical methods and linked the BP measurements with the data for cardiovascular disease and death date from the Danish registries for each person.The results showed that the American definition of hypertension has same risk for future cardiovascular disease as the definition of normal BP.This means that healthy persons will be diagnosed with hypertension if the US guidelines were applied in Denmark.

Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke: a cohort-based study.

AIMS: The atherogenic potential of cholesterol in triglyceride-rich lipoproteins, also called remnant cholesterol, is being increasingly acknowledged. Elevated remnant cholesterol is associated with increased risk of myocardial infarction and ischaemic stroke. We tested the hypothesis that elevated remnant cholesterol is also associated with increased risk of peripheral artery disease (PAD). METHODS AND RESULTS: We studied 106 937 individuals from the Copenhagen General Population Study recruited in 2003-15. During up to 15 years of follow-up, 1586 were diagnosed with PAD, 2570 with myocardial infarction, and 2762 with ischaemic stroke. We also studied 13 974 individuals from the Copenhagen City Heart Study recruited in 1976-78. During up to 43 years of follow-up, 1033 were diagnosed with PAD, 2236 with myocardial infarction, and 1976 with ischaemic stroke. Remnant cholesterol was calculated from a standard lipid profile. Diagnoses were from Danish nationwide health registries. In the Copenhagen General Population Study, elevated remnant cholesterol levels were associated with higher risk of PAD, up to a multivariable adjusted hazard ratio (HR) of 4.8 (95% confidence interval 3.1-7.5) for individuals with levels ≥1.5 mmol/L (58 mg/dL) vs. <0.5 mmol/L (19 mg/dL). Corresponding results were 4.2 (2.9-6.1) for myocardial infarction and 1.8 (1.4-2.5) for ischaemic stroke. In the Copenhagen City Heart Study, corresponding HRs were 4.9 (2.9-8.5) for PAD, 2.6 (1.8-3.8) for myocardial infarction, and 2.1 (1.5-3.1) for ischaemic stroke. CONCLUSION: Elevated remnant cholesterol is associated with a five-fold increased risk of PAD in the general population, higher than for myocardial infarction and ischaemic stroke.

Predictive value of optical coherence tomography, multifocal visual evoked potentials, and full-field visual evoked potentials of the fellow, non-symptomatic eye for subsequent multiple sclerosis development in patients with acute optic neuritis.

BACKGROUND: Diagnosis of multiple sclerosis (MS) may sometimes be ascertained at the time of optic neuritis (ON) but other times require the advent of new disease activity. OBJECTIVES: The aim of this study was to examine the predictive value of optical coherence tomography (OCT) and visual evoked potential (VEP) measurements of the non-symptomatic, fellow eye of ON patients, for conversion to MS. METHODS: This is a prospective cohort study in patients with acute ON. OCT thickness measurements of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer-inner plexiform layer (GCLIPL), and multifocal (mf) VEP and full-field (ff) VEP, were performed. Univariate and multivariate Cox regression examined the value of predictors for the conversion to MS. RESULTS: A total of 79 unilateral, acute ON patients, with no MS diagnosis or prior demyelination, were included. Of which, 28 patients developed MS during follow-up. Inferonasal GCLIPL, mean GCLIPL, and pRNFL thickness significantly predicted MS development in multivariate analysis (hazard ratio (HR) = 0.922-0.939, p = 0.0172-0.021). MfVEP mean latency (HR = 1.052, p = 0.006) only predicted MS conversion in univariate analysis. No significant predictive value was shown for the other parameters (p > 0.2). CONCLUSION: While both mfVEP and OCT are useful tools in the evaluation of acute ON patients, only OCT measurements of fellow eyes may serve as an independent predictor of MS development.

Multifocal visual evoked potential evaluation for diagnosis of acute optic neuritis and for prediction of visual outcome and ganglion cell layer thinning following optic neuritis.

BACKGROUND: While damage to the optic nerve following optic neuritis (ON) is readily quantifiable, the evaluation of prognosis for visual function and neuroaxonal loss in the acute ON is challenging. OBJECTIVE: The objective of this study is to investigate the value of multifocal visual evoked potential (mfVEP) in acute ON, diagnostically for acute ON and prognostically for visual outcome and subsequent ganglion cell/inner plexiform layer thickness (GCLIPLt). METHODS: A prospective cohort study of mfVEP and full-field visual evoked potential (ffVEP) in acute, unilateral ON (onset < 31 days) was conducted. Comparisons with healthy controls (n = 30) and association analysis with follow-up optical coherence tomography (OCT) measurements (of the GCLIPLt) and visual function (Sloan low-contrast visual acuity (LCVA)) were conducted. RESULTS: Seventy-nine ON patients were included (mean: 17 days from onset). Excluding measurements with conduction block, ffVEP (n = 54) and mfVEP (n = 44) showed sensitivities of 89% and 84% to a specificity of 97%. 65/79 patients were re-examined (mean: 200 days follow-up). mfVEP amplitude and latency inter-eye asymmetry in acute ON correlated with GCLIPLt (r = 0.587 and Spearman's ρ = 0.597, for both, p < 0.001). mfVEP amplitude correlated with LCVA inter-eye asymmetry at follow-up (r = 0.421, p < 0.001), mfVEP latency did not. CONCLUSION: mfVEP may support the prognostic evaluation of acute ON patients and prove valuable in future neuroprotective and remyelinating trials. In acute ON, the increase in diagnostic value of mfVEP to ffVEP may be limited due to widespread conduction block.

A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

OBJECTIVES: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. METHODS: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. RESULTS: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. CONCLUSIONS: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

Diastolic function assessed with speckle tracking over a decade and its prognostic value: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) may be a more accurate measure of LV filling pressure then ratio of early filling pressure to early tissue velocity. The aim of the study was to investigate the impact of age, sex, obesity, smoking, hypertension, hypercholesterolemia, diabetes, physical activity level, socioeconomic, and psychosocial status on E/e'sr over a decade. Additionally, the predictive value of ΔE/e'sr on future major adverse cardiovascular events (MACE) has never been explored. METHOD: The study included 623 participants from the general population, who participated in the 4th and 5th Copenhagen City Heart Study (CCHS4 and CCHS5). Examinations were median 10 years apart. MACE was the composite endpoint of heart failure, myocardial infarction, and all-cause death. RESULTS: Follow-up time was median 5.7 years, and 43 (7%) experienced MACE. Mean age was 51 ± 14 years, and 43% were male. Mean ΔE/e'sr was 2.1 ± 23.0 cm. After multivariable adjustment for demographic, clinical, and biochemistry variables, high age (stand. ß-coef. = .24, P < .001) and mean arterial blood pressure (MAP) (stand. ß-coef. = .17, P < .001) were significantly associated with an accelerated increase in E/e'sr In multivariable Cox regression, E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of MACE (HR = 1.20, 95% CI [1.01; 1.42] per 10 cm increase for both). ΔE/e'sr did only provide incremental prognostic value to change in left atrial volume index of the conventional diastolic measurements. CONCLUSION: In the general population, age and MAP were predictors of an accelerated increase in E/e'sr over a decade. E/e'sr at CCHS5 and ΔE/e'sr were independent predictors of future MACE.

A woman in her forties with unilateral blurred vision and pain upon eye movement. / En kvinne i 40-årene med ensidig tåkesyn og smerter ved øyebevegelse.

BACKGROUND: Toxoplasmosis is a relatively common cause of infectious papillitis and neuroretinitis, which may affect both immunocompetent and immunodeficient patients. CASE PRESENTATION: A previously healthy woman in her mid-forties presented with subacute onset of unilateral blurred vision and retrobulbar pain exacerbated by eye movements. Ophthalmological assessment revealed decimal best-corrected visual acuity of 0.75, an ipsilateral swollen disc and a peripapillary infiltrate. Serology indicated acute infection with Toxoplasma gondii. Cerebral MRI showed a periventricular lesion, and oligoclonal bands were detected in the cerebrospinal fluid. INTERPRETATION: This case illustrates that even when symptoms, MRI and cerebrospinal fluid findings suggest demyelinating disease, differential diagnoses must be considered in order to mitigate the negative therapeutic and prognostic consequences of a misdiagnosis.

Functional-structural assessment of the optic pathways in patients with optic neuritis.

BACKGROUND: The pattern-reversal visual evoked potential (pVEP) is widely used for the diagnosis of Optic Neuritis (ON), but this method has some limitations. The aim of this study was to examine the added value of multifocal visual evoked potentials (mfVEP) and spectral-domain optical coherence tomography (SD-OCT) in the diagnosis of ON in patients that exhibit a normal pVEP. METHOD: Thirty-three patients with a history of having ON and 30 sex- and age-matched healthy controls (HC) were investigated. We included patients who were suspected of having a first-time ON and in whom pVEP showed normal results. Both eyes of the patients and HC were systematically investigated with SD-OCT, visual acuity, pVEP and mfVEP. The ON-affected eyes of the patients were compared with only one randomly selected eye per person in the HC group. The fellow "non-affected" eye of patients was held as a separate group. Statistical analyses were performed (including t test, Spearman's rank-order correlation test) using SPSS Statistics, Version 24.0. RESULTS: A significant difference was found in OCT mean retinal nerve fibre layer thickness (RNFLt) between patients and HC (p = 0.013) (i.e. 84.24 (± 17.00) µm versus 93.48(± 6.44) µm). An association was detected in patients between mean inter-eye asymmetry of the RNFLt and global (averaged) mfVEP amplitude (r = 0.565, p = 0.002). When analysing mfVEP signals from sectors in the upper hemifield, a significant difference was found in mean mfVEP amplitude between patients and HC (p = 0.005). CONCLUSIONS: Abnormality is potentially measurable (via reduced RNFLt and focal analyses with mfVEP amplitude) in patients suspected of having a first episode of ON where pVEP reports no abnormality. The mfVEP and SD-OCT may together be of value as supplementary tools in diagnosing ON in this patient group.

Progression in risk factors during 36 years of follow-up and prediction of carotid intima-media thickness in a large cohort of adults with and without diabetes.

Carotid intima-media thickness (IMT) can assess the cumulative effect of atherosclerotic risk factors and provides an independent predictor of future cardiovascular (CV) risk. The aim of this study was to investigate the progression of conventional risk factors in 933 long-term survivors from a Danish cohort with and without diabetes mellitus (DM) as predictors for attained carotid IMT during 35.6 (0.7) years of follow-up. Persons who participated in the first, the last and one of the intermediate rounds of the Copenhagen City Heart Study, and who had had an ultrasound-derived measure of the carotid IMT performed at the last examination were included in the analyses. The risk factors varied between persons with and without DM during the 36 years, but the difference in blood pressure disappeared in the fifth examination, where, in addition, total cholesterol was found to be lower in persons with DM. In this cohort there were no difference in attained carotid IMT between persons with and without DM at the last examination. The following risk factors were found to best predict carotid IMT: age, maximum systolic BP, average systolic BP, average BMI, minimum BMI, sex and years of smoking. The prediction of carotid IMT was clinically poor with a root mean-squared error of prediction (RMSEP) of 0.134 mm and a 95% prediction error probability interval of (-0.22; 0.30). Furthermore, the distribution of prediction errors was skewed to the right indicating that the prediction errors were larger among persons with high carotid IMT.

Sensitive Assessment of Acute Optic Neuritis by a New, Digital Flicker Test.

BACKGROUND: The Aulhorn flicker test (AFT) previously showed promise in diagnosing acute optic neuritis (ON) albeit with suboptimal sensitivity. A new, digitalized version of the AFT (the DFT) has not previously been examined in acute ON. OBJECTIVES: To examine the sensitivity, specificity and reproducibility of the DFT in acute ON. METHOD: The DFT assesses the subjective brightness of a flickering field (1-60 Hz). In normal subjects, brightness enhancement occurs at intermediate frequencies, whereas in acute ON darkness enhancement (DE) is hypothesized. AFT and DFT measurements were obtained in acute ON patients (≤31 days from first symptom) with DE as a quantitative covariate. Reproducibility of the DFT end point was assessed in the form of an intraclass correlation. RESULTS: 30 untreated first-time acute ON patients and 55 healthy controls were examined. AFT and DFT were performed 12.7 days (range: 4-30) following ON onset. The DFT showed a sensitivity of 0.93 (95% CI = 0.78-0.99) to a specificity of 0.96 (95% CI = 0.87-1.00). The AFT showed a sensitivity of 0.76 (95% CI = 0.56-0.90) to a specificity of 1.00 (95% CI = 0.93-1.00). No significant correlation was shown between DFT and visual acuity. The intraclass correlation of the DFT end point in healthy subjects was 0.84. CONCLUSIONS: We present a new DFT in acute ON displaying a high specificity of 0.96 and a sensitivity of 0.93. Our study indicates the DFT to be an accurate and easy-to-use tool in diagnosing acute ON, which may be especially helpful in atypical cases.

Resting heart rate and mortality in the very old.

The number of very old individuals in the population is rapidly increasing. Previous studies have indicated that many factors known to be strongly associated with survival among middle-aged and elderly show no association among the oldest old. Resting heart rate (RHR) is associated with increased risk of death in the general population as well as in patients with various types of heart disease. The association between RHR and mortality in the very old is the subject of this report. The study population was identified in The Nationwide Danish 1905 Cohort Study (n = 1086) and comprised 854 subjects with a median age of 95.2 years (range 94.7-95.9), in whom RHR was measured by radial pulse palpation. Participants were followed until death through the civil registration system, and remaining lifespan after RHR measure was used as outcome. Participants were divided into six groups according to RHR (≤50, 51-60, 61-70, 71-80, 81-90 and ≥91) with the largest group used as the reference group (61-70 beats per minute (bpm)). Survival analyses using Cox' proportional hazards models were performed to study the association between RHR and mortality. Median RHR was 68 bpm in males (IQR 62-76) and 70 bpm (IQR 64-78) in females. After stratifying both sexes into six groups according to RHR, we found no significant difference in remaining lifespan between groups in either males or females. No significantly increased risk was demonstrated in groups with higher RHR. In very old people, elevated RHR is not associated with increased mortality.

Increasing population height and risk of incident atrial fibrillation: the Copenhagen City Heart Study.

Aims: The incidence of atrial fibrillation (AF) has increased significantly over the last decades. Population height is changing in many countries. Height is an important risk factor for AF. The aim of the present study was to assess the role of changes in population height in the increased risk of AF. Methods and results: The Copenhagen City Heart Study comprises 18 852 randomly selected men and women aged 20-93 years, studied in four separate cross-sectional surveys in 1976-78, 1981-83, 1991-94, and 2001-03, including physical examination, electrocardiogram (ECG), and standard questionnaires. Hospitalization and mortality data were collected from public registers. Prevalent AF was determined from ECGs and incident AF from register diagnoses. During follow-up, age-standardized prevalence of AF increased significantly from 1.35% to 2.11% in men and from 0.67% to 1.07% in women (P < 0.001). Incident AF increased four-fold in both men and women [hazard ratio (HR) 4.16, 95% confidence interval (CI) 3.27-5.29; P < 0.001]. In multivariable Fine and Gray subdistribution hazards regression analyses, height was consistently an important risk factor for incident AF with HRs between 1.35 (95% CI 1.10-1.66; P = 0.004) and 1.65 (95% CI 1.40-1.93; P < 0.001). Population height increased with 3.3 cm for men and 2.1 cm for women, and population attributable risks for height was 20-30%. Conclusion: Height is a powerful risk factor for AF. Adult height is attained at age 20, while AF incidence occurs 50 years later. Given a causal relationship between height and AF incidence, increased population height in Denmark will contribute to an increase in AF occurrence for at least 25 more years.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Resting Heart Rate Is Not Associated with Cognitive Function.

AIMS: In order to examine the hypothesis that elevated resting heart rate (RHR) is associated with impaired cognitive score, we investigated the relationship between RHR and cognitive score in middle-aged, elderly and old Danish subjects from the general population. METHODS: Composite cognitive scores derived from the result of 5 age-sensitive cognitive tests for a total of 7,002 individuals (Middle-aged Danish twin: n = 4,132, elderly Danish twins: n = 2,104 and Danish nonagenarian: n = 766) divided according to RHR and compared using linear regression models adjusted for sex, age, previous heart conditions and hypertension. RHR was assessed by palpating radial pulse. Genetic and shared environmental confounding was addressed in intrapair analyses of 2,049 twin pairs. RESULTS: In unadjusted multivariate models and in multivariable models adjusting for age, sex, heart conditions and hypertension, RHR was not associated with cognitive function. Furthermore, the intrapair analyses showed that RHR was not associated with cognitive score testing within twin pairs, as measured by the proportion of twin pairs in which the twin with higher RHR also was the twin with the lowest composite cognitive score (1,049 pairs of 2,049 pairs [51% (95% CI 49-53), p < 0.289]). CONCLUSION: While elevated RHR has been shown to be associated with adverse health events and poor fitness level, RHR has no relation to cognitive function in the general population.

Carotid intima media thickness and ankle brachial index are inversely associated in subjects with and without diabetes.

Carotid intima-media thickness (IMT) and ankle brachial index (ABI) are non-invasive indicators of generalised atherosclerosis. The aim was to determine the association between carotid IMT and ABI in subjects with and without diabetes mellitus (DM), and to analyse specific age change-points. We included 2744 subjects from the Copenhagen City Heart Study (mean age (SD) 56.6 (17.2) years, 56.8% women and body mass index (BMI) 25.4 (4.1) kg/m2). Carotid IMT and ABI measurements were performed during the fifth examination. Of the 2744 subjects, 125 subjects (4.6%) had DM. Average carotid IMT was 0.667 (0.145) mm and ABI was 1.06 (0.14). Subjects with DM were older, had higher BMI and systolic blood pressure (SBP) (all p < .001). Carotid IMT was higher in subjects with DM (0.754 (0.150) mm) compared to subjects without DM (0.662 (0.144) mm) (p < .001), whereas there was no difference in ABI between the two groups. ABI was inversely associated with carotid IMT (slope = -0.17 [-0.207; -0.137] (p < .001). The association remained significant after adjustment for risk factors both in subjects with DM (slope = -0.168 [-0.328; -0.007], p = .040), and in subjects without DM (slope = -0.100 [-0.148; -0.052], p < .001), with a stronger effect of carotid IMT on ABI among subjects with DM. Carotid IMT and ABI were inversely associated in subjects with DM and without DM, but with a stronger effect in subjects with DM. Age and ABI revealed a change-point with a stronger inverse association among subjects aged >60 years.

Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women.

OBJECTIVE: Sex hormones may be critical determinants of ischemic heart disease and death in women, but results from previous studies are conflicting. To clarify this, we tested the hypothesis that extreme plasma concentrations of endogenous estradiol and testosterone are associated with risk of ischemic heart disease and death in women. APPROACH AND RESULTS: In a nested prospective cohort study, we measured plasma estradiol in 4600 and total testosterone in 4716 women not receiving oral contraceptives or hormonal replacement therapy from the 1981 to 1983 examination of the Copenhagen City Heart Study. During ≤30 years of follow-up, 1013 women developed ischemic heart disease and 2716 died. In women with a plasma estradiol below the fifth percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk of ischemic heart disease was 44% (95% confidence interval, 14%-81%) higher; however, plasma estradiol concentrations did not associate with death. Also, in women with a plasma testosterone concentration at or above the 95th percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk was 68% (34%-210%) higher for ischemic heart disease, 36% (18%-58%) higher for any death, and 38% (15%-65%) higher for death from other causes than cardiovascular disease and cancer. These results were similar for postmenopausal women alone. CONCLUSIONS: In women, extreme low concentrations of endogenous estradiol were associated with high risk of ischemic heart disease, and extreme high concentrations of endogenous testosterone were associated with high risk of ischemic heart disease and death.

Ranking of psychosocial and traditional risk factors by importance for coronary heart disease: the Copenhagen City Heart Study.

AIMS: To rank psychosocial and traditional risk factors by importance for coronary heart disease. METHODS AND RESULTS: The Copenhagen City Heart Study is a prospective cardiovascular population study randomly selected in 1976. The third examination was carried out from 1991 to 1994, and 8882 men and women free of cardiovascular diseases were included in this study. Events were assessed until April 2013. Forward selection, population attributable fraction, and gradient boosting machine were used for determining ranks. The importance of vital exhaustion for risk prediction was investigated by C-statistics and net reclassification improvement. During the follow-up, 1731 non-fatal and fatal coronary events were registered. In men, the highest ranking risk factors for coronary heart disease were vital exhaustion [high vs. low; hazard ratio (HR) 2.36; 95% confidence interval (CI), 1.70-3.26; P < 0.001] and systolic blood pressure (≥160 mmHg or blood pressure medication vs. <120 mmHg; HR 2.07; 95% CI, 1.48-2.88; P < 0.001). In women, smoking was of highest importance (≥15 g tobacco/day vs. never smoker; HR 1.74; 95% CI, 1.43-2.11; P < 0.001), followed by vital exhaustion (high vs. low; HR 2.07; 95% CI, 1.61-2.68; P < 0.001). Vital exhaustion ranked first in women and fourth in men by population attributable fraction of 27.7% (95% CI, 18.6-36.7%; P < 0.001) and 21.1% (95% CI, 13.0-29.2%; P < 0.001), respectively. Finally, vital exhaustion significantly improved risk prediction. CONCLUSION: Vital exhaustion was one of the most important risk factors for coronary heart disease, our findings emphasize the importance of including psychosocial factors in risk prediction scores.

Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013.

IMPORTANCE: Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed. OBJECTIVE: To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades. DESIGN, SETTING, AND PARTICIPANTS: Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13,704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first. EXPOSURES: For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared. MAIN OUTCOMES AND MEASURES: Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality. RESULTS: The number of deaths during follow-up was 10,624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95%CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95%CI, 9-30]), and 5580 in the 2003-2013 cohort (6%;MR, 4/1000 person-years [95%CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI associated with the lowest all-cause mortality increased by 3.3 from the 1976-1978 cohort compared with the 2003-2013 cohort. [table: see text] The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95%CI, 1.23-1.39;MR, 46/1000 person-years [95%CI, 32-66] vs 28/1000 person-years [95%CI, 18-45]) in the 1976-1978 cohort, 1.13 (95%CI, 1.04-1.22; MR, 28/1000 person-years [95%CI, 17-47] vs 15/1000 person-years [95%CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95%CI, 0.92-1.07;MR, 5/1000 person-years [95%CI, 2-12] vs 4/1000 person-years [95%CI, 1-11]) in the 2003-2013 cohort. CONCLUSIONS AND RELEVANCE Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications.

Visible age-related signs and risk of ischemic heart disease in the general population: a prospective cohort study.

BACKGROUND: Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. METHODS AND RESULTS: 10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57 (1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. CONCLUSIONS: Male pattern baldness, earlobe crease, and xanthelasmata-alone or in combination-associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health.

Agreement between public register and adjudication committee outcome in a cardiovascular randomized clinical trial.

UNLABELLED: The objective of this study is to describe the agreement between randomized trial outcome assessment by committee and outcomes entirely identified through public registers. METHODS: In the CLARICOR trial, 4,372 patients with stable coronary heart disease received a short course of clarithromycin versus placebo and were followed up for 2.6 years. The pertinent hospital records and death certificates had originally been evaluated by the adjudication committee using common definitions of outcomes mapped into a 6-category list. We now mechanically converted the International Classification of Diseases-coded diagnoses of the public registries into the same categories. After cross-tabulation of the committee diagnoses with National Patient Register diagnoses and Register of Causes of Death, we calculate agreement and compare the estimated intervention effects of the 2 data sets. RESULTS: With public register data, the protocol-specified categories were slightly more frequent. Overall agreement was 74% for hospital discharges and 60% for cause of death, but the intervention effect, expressed as a hazard ratio, stayed within 4% of the value originally obtained with the adjudication committee (P ≥ .35). CONCLUSIONS: Our results show a modest agreement between formal adjudication and outcomes deducible from public registers. However, the estimated intervention effect did not differ noticeably between the 2 data sources. If studies on a wide range of public registers confirm these findings, register outcomes may be considered as a replacement for adjudication committees.