Preman Kumarathurai

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.

Effects of Liraglutide on Heart Rate and Heart Rate Variability: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

OBJECTIVE Reduced heart rate variability (HRV) and increased heart rate (HR) have been associated with cardiovascular mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) increase HR, and studies have suggested that they may reduce HRV. We examined the effect of the GLP-1 RA liraglutide on HRV and diurnal variation of HR in overweight patients with newly diagnosed type 2 diabetes (T2D) and stable coronary artery disease (CAD). RESEARCH DESIGN AND METHODS Liraglutide or placebo was administrated to a backbone therapy of metformin in this double-blind, placebo-controlled 12 + 12–week crossover study. SD of beat-to-beat (NN) intervals (SDNN) was assessed by 24-h Holter monitoring as a measure of HRV. Diurnal HR variation and sympathovagal balance analyzed by root mean square of successive differences (RMSSD) in NN intervals and high-frequency (HF) and low-frequency (LF) power were assessed. RESULTS Compared with placebo, liraglutide decreased SDNN in 27 subjects (−33.9 ms; P < 0.001, paired analysis); decreased RMSSD (−0.3 log-ms; P = 0.025); and increased the mean HR (8.1 beats/min; P = 0.003), daytime HR (5.7; P = 0.083), and nighttime HR (6.3; P = 0.026). In a multivariable regression analysis, the decrease in SDNN remained significant after adjustment for metabolic and HR changes. Liraglutide reduced HF power (−0.7 log-ms2; P = 0.026) without any change in LF/HF ratio. CONCLUSIONS In overweight patients with CAD and newly diagnosed T2D, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters. The increase in nightly HR in conjunction with a decrease in parameters of parasympathetic activity suggests that liraglutide may affect sympathovagal balance.

Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: a randomized, double-blind, placebo-controlled, crossover study.

Objective: The glucagon-like peptide-1 receptor agonist liraglutide has been shown to reduce blood pressure (BP) in clinical trials using office BP measurements. However, the effects of liraglutide on 24-h BP and on the diurnal variation in BP have not been explored sufficiently. Methods: Forty-one patients with type 2 diabetes and stable coronary artery disease were randomized to receive liraglutide or placebo to a backbone therapy of metformin in this double-blind, placebo-controlled 12 along with 12 weeks crossover study. Ambulatory blood pressure monitoring (ABPM) was performed at the start and end of each intervention. Results: Twenty-four individuals completed all 24-h BP measurements. Liraglutide, when compared with placebo, did not induce any significant changes in mean 24-h SBP [difference +1.8 mmHg (95% confidence interval, 95% CI: −4.33 to 7.93)] or DBP [+4.2 mmHg (−0.74 to 9.17)]. Twenty-four-hour BP profiles revealed a trend for increase in evening SBP and DBP [+9.2 mmHg (95% CI: 1.1–17.2) and +9.7 mmHg (95% CI: 3.9–15.5), respectively]. Mean heart rate significantly increased after liraglutide [+7.6 bpm (95% CI: 2.56–12.62)]. Liraglutide did not affect the BP variability or the nocturnal BP dipping. Conclusions: We could not demonstrate any BP-lowering effect of liraglutide when using 24-h ABPM. Liraglutide exhibited diurnal variation in the effect on BP without affecting the BP variability or nocturnal BP dipping.

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.

Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study): a randomised controlled study protocol.

Introduction Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve β-cell function and left ventricular systolic function during dobutamine stress. Methods and analyses 40 patients with CAD and newly diagnosed T2DM will receive the intervention liraglutide+metformin and placebo+metformin in this investigator-initiated, double blind, randomised, placebo-controlled, cross-over 12 plus 12 weeks intervention study with a 2-week washout period. The primary cardiovascular end point is changes in left ventricular ejection fraction during stress echocardiography. The primary endocrine end point is β-cell function evaluated during a frequently sampled intravenous glucose tolerance test. Secondary end points include heart rate variability, diurnal blood pressure, glucagon suppression and inflammatory response (urine, blood and adipose tissue). Ethics and dissemination This study is approved by the Danish Medicines Agency, the Danish Dataprotection Agency and the Regional Committee on Biomedical Research Ethics of the Capital Region of Denmark. The trial will be carried out under the guidance from the GCP unit at Copenhagen University Hospital of Bispebjerg and in accordance with the ICH-GCP guidelines and the Helsinki Declaration. Trial registrations number Clinicaltrials.gov ID: NCT01595789, EudraCT: 2011-005405-78.

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.

Long-term prognostic significance of homocysteine in middle-aged and elderly

Abstract Objective: We investigated the association among increased levels of plasma homocysteine (Hcy), all-cause mortality, and cardiovascular events. Methods: Hcy was measured in 670 middle-aged and elderly subjects with no previous manifest cardiovascular disease. The follow-up period was 15 years. Results: Subjects with Hcy ≥ 10.8 μmol/l (n = 231) had a significant higher incidence of all-cause mortality (p < 0.001) and CV events (p < 0.001) compared with subjects with Hcy < 10.8 μmol/l (n = 439). However, there was no association on high levels of Hcy and VTE events or stroke. Conclusion: Increased levels of Hcy are associated with all-cause mortality and CV events.

Liraglutide effects on beta-cell, insulin sensitivity and glucose effectiveness in patients with stable coronary artery disease and newly diagnosed type 2 diabetes.

The aims of the study were to investigate the effects of the GLP‐1 receptor agonist liraglutide as add‐on to metformin on insulin sensitivity (Si) and glucose effectiveness (Sg) in addition to its positive effects on beta‐cell function in overweight/obese patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM).

Mild Hypokalemia and Supraventricular Ectopy Increases the Risk of Stroke in Community-Dwelling Subjects

Background and Purpose— Stroke is independently associated with the common conditions of hypokalemia and supraventricular ectopy, and we hypothesize that the combination of excessive supraventricular ectopic activity and hypokalemia has a synergistic impact on the prognosis in terms of stroke in the general population. Methods— Subjects (55–75 years old) from the Copenhagen Holter Study cohort (N=671) with no history of atrial fibrillation or stroke were studied—including baseline values of potassium and ambulatory 48-hour Holter monitoring. Excessive supraventricular ectopic activity is defined as ≥30 premature atrial complexes per hour or any episodes of runs of ≥20. Hypokalemia was defined as plasma-potassium ⩽3.6 mmol/L. The primary end point was ischemic stroke. Cox models were used. Results— Hypokalemia was mild (mean, 3.4 mmol/L; range, 2.7–3.6). Hypokalemic subjects were older (67.0±6.94 versus 64.0±6.66 years; P<0.0001) and more hypertensive (165.1±26.1 versus 154.6±23.5 mm Hg; P<0.0001). Median follow-up time was 14.4 years (Q1–Q3, 9.4–14.7 years). The incidence of stroke was significantly higher in the hypokalemic group (hazard ratio, 1.84; 95% confidence interval, 1.04–3.28) after covariate adjustments, as well as in a competing risk analysis with death (hazard ratio, 1.51; 95% confidence interval, 1.12–2.04). Excessive supraventricular ectopic activity was also associated with stroke (hazard ratio, 2.23; 95% confidence interval, 1.33–3.76). The combination of hypokalemia and excessive supraventricular ectopic activity increased the risk of events synergistically. Stroke rate was 93 per 1000 patient-year (P<0.0001) in this group (n=17) compared with 6.9 (n=480); 11 (n=81), and 13 (n=93) per 1000 patient-year in the groups without the combination. Conclusions— The combination of hypokalemia and excessive supraventricular ectopy carries a poor prognosis in terms of stroke.

[OP.4A.09] THE EFFECT OF THE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST LIRAGLUTIDE ON 24-H BLOOD PRESSURE VARIATION: A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED CROSS OVER STUDY

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown to reduce blood pressure in some clinical trials. Only a few studies have examined the effect of GLP-1 RAs on the 24-h variation of blood pressure. In this study, we explored the effect of the GLP-1 RA liraglutide on 24-h blood pressure and heart rate (HR) variation in patients with type 2 diabetes (T2DM) and coronary artery disease (CAD). Figure. No caption available. Design and method: Forty-one subjects were randomized to liraglutide plus metformin or placebo plus metformin in this this double-blind, placebo-controlled 12 plus 12 weeks cross-over study. Subjects underwent 24-h ambulatory blood pressure monitoring at start and end of each period. Results: Twenty-four subjects completed all ambulatory blood pressure measurements. Liraglutide, when compared to placebo, did not induce any significant changes in mean 24-h systolic (+1.8 mmHg, p = 0.549; 95% CI: −4.3 to 7.9) or diastolic blood pressure (+4.2 mmHg, p = 0.09; 95% CI [−0.7 to 9.2]. Evening (7 pm to 12 pm) systolic and diastolic blood pressure was elevated after liraglutide treatment as compared to placebo (+9.2 mmHg, p = 0.028; 95% CI [1.1. to 17.2] and +9.7 mmHg, p = 0.002; 95% CI [3.9 to 15.5], respectively). Changes in blood pressure were not correlated to changes in weight during liraglutide or placebo. Mean HR was significantly increased (+7.6 bpm; p = 0.005; 95% CI: 2.6 to 12.6). Conclusions: In patients with T2DM and CAD, 12 weeks of liraglutide treatment increased 24-h mean HR, but did not change mean diurnal blood pressure significantly as compared to placebo. However, liraglutide lead to significantly higher evening systolic and diastolic blood pressure as compared to placebo. The pathophysiological explanation for this observation needs to be explored in further studies.