Mette Rauhe Mouridsen

Resting, night-time, and 24 h heart rate as markers of cardiovascular risk in middle-aged and elderly men and women with no apparent heart disease

AIMS Increased heart rate (HR) is a predictor of all-cause and cardiovascular (CV) mortality. We tested which measure of HR had the strongest prognostic value in a population with no apparent heart disease. METHODS AND RESULTS Six hundred and fifty-three men and women between the age of 55 and 75 years were included in the Copenhagen Holter Study and underwent 48 h ambulatory electrocardiographic (ECG) monitoring. Resting HR was measured after at least 10 min of rest. Twenty-four-hour HR was derived from the mean time between normal-to-normal RR intervals (MEANNN). Night-time HR was derived from a 15 min sequence between 2:00 and 2:15 a.m. The median follow-up time was 76 months, and an adverse outcome was defined as all-cause mortality and the combined endpoint of CV death, acute myocardial infarction (AMI), and revascularization. All three measures of HR were significantly associated with all-cause mortality, also after adjustment for conventional risk factors. We found an association between all three measures of HR and CV events in analyses adjusted for sex and age. However, when adjusting for CV risk factors, the association with resting HR and 24 h HR disappeared. In a fully adjusted model, only night-time HR remained in the model, hazard ratio = 1.17 (1.05-1.30), P = 0.005. CONCLUSION In middle-aged subjects with no apparent heart disease, all measures of increased HR were associated with increased mortality and CV risk. However, night-time HR was the only parameter with prognostic importance after multivariable adjustment.

Decreased Nighttime Heart Rate Variability Is Associated With Increased Stroke Risk

Background and Purpose— Prediction of stroke in healthy individuals is challenging and there is a diurnal variation of stroke onset. We hypothesized that heart rate variability with a focus on nighttime heart rate variability will predict the risk of stroke in apparently healthy middle-age and elderly subjects. Methods— The population-based cohort of the Copenhagen Holter Study, consisting of 678 healthy subjects between age 55 and 75 years with no history of cardiovascular disease or stroke, was evaluated. All underwent 48-hour ambulatory electrocardiogram monitoring. The SD of normal-to-normal RR intervals (SDNN) was selected as the method of measuring heart rate variability. Nighttime SDNN was measured between 02:00 and 02:15 AM and could be evaluated in 653 subjects. Median follow-up was 76 months. Results— Nighttime SDNN was lower in women than in men (P=0.0008), and in diabetics than nondiabetics (P=0.03). However, smoking, cholesterol, systolic blood pressure, and age were not associated with nighttime SDNN. The risk of stroke was significantly associated with nighttime SDNN in a univariate analysis (HR, 0.66; 95% CI, 0.50–0.88; P=0.004) and after adjustment for conventional risk factors (HR, 0.67; 95% CI, 0.51–0.89; P=0.005) per 10 ms increments of SDNN. Eighty-one percent of all strokes (21/26) occurred in 330 subjects with the lower half of nighttime SDNN (⩽38 ms; HR, 4.31; 95% CI, 1.62–11.42; P=0.003). Conclusions— Nocturnal heart rate variability is a strong marker for the development of stroke in apparently healthy subjects. The mechanism is unknown, but reduced parasympathetic activity may increase the risk of stroke by increasing the risk of arrhythmias.

NT-ProBNP Independently Predicts Long-Term Mortality in Patients Admitted for Coronary Angiography

Recently, research interests are focussed on biomarkers to predict the outcome in patients with coronary artery disease (CAD). We examined whether the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) could predict outcome in patients who underwent elective or acute coronary angiography (CAG). A total of 337 patients with suspected CAD who underwent elective or acute CAG were followed up for a mean period of 6.7 years. Primary end points were all-cause mortality (ACM) and the combined end point of ACM, nonfatal myocardial infarction, and revascularization. In all, 53 (16%) patients died and 88 (26%) patients reached the combined end point. Preprocedural NT-proBNP above 32 pmol/L independently predicted ACM (hazard ratio [HR] 3.11; confidence interval [CI]: 1.60-6.07; P = .001) and the combined end point (HR 2.44 [CI: 1.50-3.97]; P < .001). This study indicates that high NT-proBNP is an independent predictor of ACM on long-term follow-up. N-terminal-proBNP is a reliable predictive marker of mortality in the setting of stable or unstable angina.

Soluble urokinase plasminogen activator receptor, C-reactive protein and triglyceride are associated with heart rate variability in non-diabetic Danes.

Heart rate variability (HRV) is associated with an increased risk of cardiovascular morbidity and mortality. HRV is in part a function of the activity of the autonomic nervous system and has been associated with low‐grade inflammation. In patients with type 2 diabetes, HRV is decreased and is a predictor of poor outcome. As HRV and its determinants in non‐diabetic individuals have not been studied properly, the aim of this observational study was to evaluate possible associations between HRV vs. impaired fasting glucose, insulin resistance, lipidaemia and markers of inflammation and immune activation in these individuals.

Monocyte number associated with incident cancer and mortality in middle-aged and elderly community-dwelling Danes

BACKGROUND Monocytes play an important role in innate immunity and exhibit prognostic value in some cancers. It was hypothesised that activation of the innate immune system through mobilisation of monocytes to tissue macrophages develops an inflammatory state associated with increased risk of cancer and mortality. METHODS To test this hypothesis monocyte number was measured in a sample of 669 Danish men (59%) and women (41%) aged 55 to 75 years who were free of any known prevalent cancer or cardiovascular disease. The population was followed for 6.3 years, during which period incident cancers and deaths were compiled from validated national registries. RESULTS Fifty-two subjects developed cancer and 83 subjects died during follow-up. The upper quintile of monocyte number (median 0.44×10⁹/L, lower quintile <0.33, upper quintile >0.60) was associated with an increased risk of cancer (hazard ratio [HR] 2.00 [95% CI 1.12-3.57]) and deaths (HR 1.67 [1.03-2.72]) in univariate analyses, after correction for age and gender (cancer HR 2.15 [1.20-3.86] and death HR 1.63 [1.00-2.67]), and following additional correction for smoking habits, diabetes, systolic blood pressure, and total cholesterol (cancer HR 2.00 [1.10-3.70] and death HR 1.30 [0.78-2.16]). COX regression models, with inclusion of the aforementioned explanatory variables and added heart rate variability, alcohol use, and CRP, revealed monocyte count (per 0.1×10⁹/L increase) to be independently associated with incident cancer (HR 1.12 (1.05-1.19)) and death (HR 1.13 (1.06-1.19)). CONCLUSIONS In healthy middle-aged and elderly community-dwelling Danes circulating monocytes independently predicted incident cancer and mortality.

High-sensitivity C-reactive protein and exercise-induced changes in subjects suspected of coronary artery disease

Background Inflammation plays a major role in the development of atherosclerosis. We wanted to investigate the effects of exercise on high-sensitivity (hs) C-reactive protein (CRP) in subjects who were suspected of having coronary artery disease (CAD). Methods Blood samples were obtained before, 5 minutes after, and 20 hours after an exercise test in 155 subjects who were suspected of CAD. Coronary anatomy was evaluated by computed tomography coronary angiography and/or coronary angiography. Results Median baseline hs-CRP was higher in subjects with ≥50% coronary artery lumen diameter stenosis (n=41), compared with non-CAD-subjects (n=114), 2.93 mg/L (interquartile range 1.03–5.06 mg/L) and 1.30 mg/L (interquartile range 0.76–2.74 mg/L), respectively, P=0.007. In multivariate analyses testing conventional risk factors, hs-CRP proved borderline significant, odds ratio =2.32, P=0.065. Adding baseline hs-CRP to the results of the exercise test did not improve the diagnostic evaluation. Baseline natural logarithm (Ln) hs-CRP was positively associated with body mass index and baseline Ln-transformed hs troponin T levels, and negatively associated with the daily life activity level. An increase in hs-CRP of 0.13 mg/L (interquartile range 0.05–0.24 mg/L) from baseline to 5 minutes after peak exercise was found (P<0.0001), but the increase was not associated with presence of CAD. From baseline to 20 hours after exercise, no increase in hs-CRP was found. Conclusion In conclusion, hs-CRP was not independently associated with CAD. Hs-CRP increased immediately as a response to the exercise, and the increase was modest and not associated with CAD. The results indicate that exercise has potential to cause unwanted variations in hs-CRP and that exercise prior to hs-CRP measurements in subjects included in epidemiological studies, therefore, should be avoided.

Modest weight loss in moderately overweight postmenopausal women improves heart rate variability

Purpose: To evaluate the effects of weight loss on heart rate (HR) and heart rate variability (HRV) parameters in overweight postmenopausal women. Design and Methods: Forty-nine overweight postmenopausal women with an average body mass index of 28.8 ± 1.9 kg/m2 underwent a 12-week dietary weight-loss programme. Accepted variables for characterization of HRV were analysed before and after the weight loss by 24-h ambulatory ECG monitoring; mean and standard deviation for the time between normal-to-normal complexes (MeanNN and SDNN, respectively), and the mean of standard deviations of normal-to-normal intervals for each 5-min period (SDNNindex). Baseline body fat mass (FM%) and changes in body composition was determined by dual X-ray absorptiometry. Before and after the weight-loss period, total abdominal fat, intra-abdominal fat (IAAT), and subcutaneous abdominal fat (SCAT) were measured by single-slice MRI at L3. Results: The weight loss of 3.9 ± 2.0 kg was accompanied by an improvement of HRV. SDNN increased by 9.2% (p = 0.003) and SDNNindex increased by 11.4% (p = 0.0003). MeanNN increased by 2.4%, reflecting a decrease in mean heart rate from 74.1 to 72.3 beats/min (p = 0.033). Systolic blood pressure (SBP) decreased by 2.7%, total cholesterol by 5.1% and high-sensitivity C-reactive protein (hsCRP) by 15.8% (p = 0.002). Improvements in SDNN and cholesterol were correlated with weight loss (r = −0.329, p = 0.024 and r = 0.327, p = 0.020, respectively) but changes in HR, SBP, and hsCRP were not. IAAT and the IAAT/SCAT-ratio were found to be negatively associated with HRV parameters but changes in body composition were not associated with changes in HRV. Conclusions: The observed improvement of HRV seems to be facilitated by weight loss. IAAT and the IAAT/SCAT ratio were found to be associated with low HRV.

Atrial ectopy and N-terminal pro-B-type natriuretic peptide as predictors of atrial fibrillation: a population-based cohort study

Aims The risk of incident atrial fibrillation (AF) can be estimated by clinical parameters in the Framingham AF risk model. Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and increased rate of premature atrial contractions (PACs) have been shown to be associated with AF, but the additive value of both of these biomarkers in the Framingham AF risk model has not been fully examined. Methods and results A total of 646 subjects from the Copenhagen Holter Study (mean age 64.4 ± 6.8 years, 41.6% women) with no history of prior AF, stroke or cardiovascular disease were followed for the diagnosis of incident AF or death (median follow-up time 14.4 years). Median NT-proBNP was 6.7 pmol/L (IQR: 3.6-13.5), median PAC count was 1.4 beats/h (IQR: 0.6-4.5), 71 (11.0%) subjects developed AF, and 244 (37.8%) died. Multiple Cox regression including Framingham AF risk score, log-transformed NT-proBNP, and log-transformed PAC showed a significant increase in AF hazard risk [hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.14-1.85, P = 0.002; HR 1.23, 95% CI 1.09-1.39, P = 0.001]. The addition of PAC to the Framingham AF risk model significantly improved the time-dependent area under the receiver operating characteristic curve (AUC 65.6 vs. 72.6; P = 0.008), while the addition of NT-proBNP did not. Conclusion Atrial fibrillation risk discrimination was significantly improved by the addition of PAC to the Framingham AF risk model, but not by the addition of NT-proBNP.

Diagnostic value of exercise-induced changes in circulating high sensitive troponin T in stable chest pain patients

Abstract Objective: We investigated the diagnostic value of exercise-induced increase in cardiac Troponin T (cTnT) in stable chest pain subjects. Methods: CTnT was measured before and 20 h after an exercise test in 157 subjects suspected of coronary artery disease (CAD). Results: CAD subjects (n = 41) had higher baseline cTnT levels compared to non-CAD subjects (n = 116), 6.39 ng/l and 3.00 ng/l, respectively, p < 0.0001, and were more likely to increase in cTnT (70.7% versus 27.6%, p < 0.0001). Net Reclassification Index for the combined variable was 19%, p = 0.02. Conclusions: Exercise-induced increase in cTnT was found to be associated with CAD and cTnT measurements improved the diagnostic evaluation.

Prognostic value of high sensitive C-reactive protein in subjects with silent myocardial ischemia

OBJECTIVES The aim of this study was to evaluate the prognostic value of high sensitive C-reactive protein (CRP) in subjects with silent myocardial ischemia (SMI). DESIGN In total, 678 healthy men and women aged 55 to 75 years with no history of cardiovascular disease or stroke were included. High-sensitive CRP and 48-hour ambulatory ECG monitoring were performed. The primary endpoint was the combined endpoint of death and myocardial infarction. RESULTS The median follow-up time was 76 months. Seventy-seven subjects (11.4%) had SMI. The combined endpoint occurred in 26% of the subjects with SMI and 14% of the subjects without SMI (P = .005). SMI had a poor prognosis in the group with an elevated CRP ≥ 3.0 μg/mL (hazard ratio, 3.46; 95% confidence interval, 1.67-7.16; P = .001) compared with the group of subjects with SMI and a low CRP <3.0 μg/mL (hazard ratio, 1.37; 95% confidence interval, 0.63-2.98; P = .54). CONCLUSIONS In apparently healthy subjects, a low level of CRP <3.0 μg/mL selects a low-risk subgroup, despite the presence of SMI.