Camilla Asferg

Leptin, Not Adiponectin, Predicts Hypertension in the Copenhagen City Heart Study

BACKGROUND Leptin and adiponectin are hormones secreted by adipose tissue, and both hormones are candidate intermediaries between adipose tissue and overweight-related diseases. So far, no prospective study has been published where the independent effects of these two hormones on the development of hypertension have been directly compared. The objective of this study was to investigate the relationships between plasma levels of leptin and adiponectin and new-onset hypertension in the Copenhagen City Heart Study (CCHS). METHODS In a prospective study design, we examined new-onset hypertension in 620 women and 300 men who were normotensive in the third CCHS examination, which was performed in 1991-1994. RESULTS Between the third and the fourth CCHS examination, which was performed in 2001-2003, 254 had developed hypertension, defined as systolic blood pressure (SBP) > or = 140 mm Hg, or diastolic blood pressure (DBP) > or = 90 mm Hg, or use of antihypertensive medication. Using logistic regression analysis, adjusting for age, sex, estimated glomerular filtration rate, triglycerides, high-density lipoprotein cholesterol (HDL-C), fibrinogen, and glucose, and with leptin and adiponectin included in the same model, leptin was significantly associated with new-onset hypertension with an odds ratio (95% confidence interval) of 1.28 (1.08-1.53; P < 0.005) for 1 s.d. higher level of log-transformed leptin, whereas adiponectin was not significantly associated with new-onset hypertension having an odds ratio of 1.02 (0.84-1.24; P = 0.83) for 1 s.d. higher level of log-transformed adiponectin. CONCLUSIONS In the CCHS, leptin, but not adiponectin, was a significant independent predictor of new-onset hypertension.

Relative Atrial Natriuretic Peptide Deficiency and Inadequate Renin and Angiotensin II Suppression in Obese Hypertensive Men

Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin–angiotensin system in 63 obese hypertensive men (obeseHT: body mass index, ≥30.0 kg/m2; 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m2; 24-hour ambulatory blood pressure, <130/80 mm Hg), and in 27 lean normotensive men (leanNT: body mass index, 20.0–24.9 kg/m2; 24-hour ambulatory blood pressure, <130/80 mm Hg). All study subjects were medication free. As a surrogate estimate for dietary sodium intake, we measured sodium excretion in a 24-hour urine collection and we measured serum levels of midregional proatrial NP and plasma levels of renin and angiotensin II. The obese men had higher mean (±SD) urinary sodium excretion (obeseHT, 213.6±85.2 mmol; obeseNT, 233.0±70.0 mmol) than the lean normotensive men (leanNT, 155.5±51.7 mmol; P=0.003). ObeseHT had lower (median [interquartile range]) serum midregional proatrial NP levels (49.2 [37.3–64.7] pmol/L) than leanNT (69.3 [54.3–82.9] pmol/L; P=0.003), whereas obeseNT had midregional proatrial NP levels in between (54.1 [43.2–64.7] pmol/L); obeseNT had lower (median [interquartile range]) plasma levels of renin (5.0 [3.0–8.0] mIU/L versus 9.0 [4.0–18.0]) and angiotensin II (2.4 [1.5–3.5] pmol/L versus 4.2 [2.2–7.9]) than obeseHT (P⩽0.049), whereas obeseHT had similar plasma levels of renin and angiotensin II as leanNT (P≥0.19). Thus, despite a high sodium intake and a high blood pressure, obese hypertensive men have a relative NP deficiency and an inadequate renin–angiotensin system suppression.

Accuracy of multi-slice computed tomography for measurement of left ventricular ejection fraction compared with cardiac magnetic resonance imaging and two-dimensional transthoracic echocardiography: a systematic review and meta-analysis.

BACKGROUND Multi-slice computed tomography (MSCT) allows non-invasive assessment of the coronary arteries and simultaneously can provide measurement of left ventricular ejection fraction (LVEF). The accuracy of newer MSCT generations (64-slice or more) for assessment of LVEF compared with magnetic resonance imaging (MRI) and two-dimensional transthoracic echocardiography (TTE) has not been evaluated in a meta-analysis. PURPOSE To evaluate, via a systematic literature review and meta-analysis, whether MSCT can assess LVEF with high accuracy compared with MRI and TTE. METHODS Electronic databases and reference lists for relevant published studies were searched. Twenty-seven eligible studies provided mean LVEF% with its standard deviation (SD) measured by MSCT versus MRI and TTE. Meta-analysis of weighted mean difference (WMD) and Bland-Altman method were used to quantify the mean difference and agreement between MSCT compared with MRI and TTE. RESULTS The results of combining 12 studies showed no significant difference in LVEF% between MSCT and MRI with a WMD of -0.11 (-1.48, 1.26, 95% CI), p=0.88. Bland-Altman analysis showed excellent agreement between MSCT and MRI with a bias of 0.0 (-3.7, 3.7 ± 1.96SD) with 95% CI. The results of combining 15 studies showed no significant difference in LVEF between MSCT versus TTE measurements with a WMD of 0.19 (-1.13 to 1.50; 95% CI), p=0.87. Bland-Altman analysis showed excellent agreement between MSCT and TTE with a bias of 0.3 (-4.7, 5.7 ± 1.96SD) with 95% CI. CONCLUSION The newer MSCT generations can provide accurate LVEF measurement compared to MRI and TTE. MSCT represents a valid technique for the combined evaluation of LVEF and coronary artery disease.

Metabolic rather than body composition measurements are associated with lower serum natriuretic peptide concentrations in normal weight and obese men.

BACKGROUND Several studies have shown that obese persons have lower circulating natriuretic peptide (NP) concentrations. The cause of the relative NP deficiency seen in obese persons is poorly understood, although variation in body composition and metabolic abnormalities has been suggested to play a role. Thus, the aim of this study was to assess whether variation in circulating NP concentrations would be associated with differences in metabolic disturbances rather than with differences in body composition. METHODS In 27 normal weight men (body mass index (BMI) = 20.0-24.9kg/m(2)) and 103 obese men (BMI ≥ 30kg/m(2)), we determined body composition (total, android, and gynoid fat mass) by dual energy x-ray absorptiometry scanning, and we measured fasting serum concentrations of midregional proatrial NP (MR-proANP) and insulin, as well as fasting plasma glucose concentrations. RESULTS Mean weight ± SD was 74.9±6.7kg in the normal weight men and 106.1±10.8kg in obese men. Applying multiple regressions, adjusting for age and weight status (normal weight vs. obese), serum MR-proANP concentrations were significantly inversely associated with serum insulin concentrations (β = -0.39; P < 0.0001) and plasma glucose concentrations (β = -0.21; P = 0.02) but not with total (β = 0.00), android (β = -0.01), or gynoid (β = 0.03) fat mass percentage (P > 0.76). No significant interaction effects between metabolic measurements or body composition measurements and weight status on MR-proANP concentrations were found (P > 0.08). CONCLUSIONS In normal weight and obese men, lower circulating NP concentrations are associated with higher insulin and glucose concentrations and not with the proportion of total fat mass or the distribution of fat mass.

Copeptin, a surrogate marker for arginine vasopressin secretion, is associated with higher glucose and insulin concentrations but not higher blood pressure in obese men

To explore the putative associations of plasma copeptin, the C‐terminal portion of provasopressin and a surrogate marker for arginine vasopressin secretion, with obesity‐related health problems, such as hyperlipidaemia, hyperinsulinaemia, hyperglycaemia, high blood pressure and an android fat distribution.

Interaction between leptin and leisure-time physical activity and development of hypertension

Abstract Objective. The mechanisms by which overweight and physical inactivity lead to hypertension are complex. Leptin, an adipocyte-derived hormone, has been linked with hypertension. We wanted to investigate the relationship between leptin, physical activity and new-onset hypertension. Methods. The study was a prospective cohort study of 744 women and 367 men, who were normotensive in the third Copenhagen City Heart Study (CCHS) examination, performed 1991–94. Based on questionnaire items, the participants were divided into two groups with low (n = 674) and high (n = 437) levels of leisure-time physical activity, respectively. Results. Between the third and the fourth CCHS examination, performed 2001–03, 304 had developed hypertension, defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg or use of antihypertensive medication. In a logistic regression model, including age, sex, body mass index, SBP, DBP, level of physical activity and leptin, we found a significant interaction between leptin and level of physical activity with new-onset hypertension as outcome variable (p = 0.012). When we entered the interaction variables, effect of leptin with low level of physical activity and with high level of physical activity, respectively, in the original model, leptin predicted new-onset hypertension in participants with low level of physical activity [odds ratio (95% confidence interval): 1.16 (1.01–1.33) for one unit increase in log-transformed leptin levels, p = 0.038], but not in participants with high level of physical activity [0.88 (0.74–1.05), p = 0.15]. Conclusion. We found that leptin predicted new-onset hypertension but only in participants with low level of physical activity.

Positive Relationship Between Plasma Leptin Levels and Hypertension From an Epidemiological Perspective

It is well-documented that a higher body mass index (BMI) is associated with a greater risk of hypertension, even among those with a BMI within the “normal” range.1,2 Also, from the field of population sciences, it has been shown that it is a higher BMI caused by fat accumulation, and not by muscle growth, that is the problem. Thus, in a prospective study of >3000 subjects, it was a higher fat mass, and not a higher fat-free mass, that was associated with a greater risk of hypertension.2 So, how does fat tissue lead to hypertension? In this context, there has been a change in the way we look at the functions of fat tissue. The traditional view of fat tissue as a passive reservoir for energy storage is no longer valid.3 On the contrary, fat tissue is an active metabolic and endocrine organ that secretes hormones and cytokines with vascular and inflammatory effects.3 These hormones and cytokines are described as adipocytokines, and because of the close relationship between overweight and various diseases, these adipocytokines are regarded as possible intermediaries between fat tissue and adiposity-related diseases, including hypertension.4 Leptin is one such adipocytokine.3 Leptin is primarily secreted by fat cells in proportion to fat cell mass. Thus, in a human study, the correlation coefficient for the association between serum leptin levels and percentage of body fat was found to be as high as 0.85, a figure that was higher than the correlation coefficient found for the association between leptin levels and BMI ( r =0.66).5 So, no matter what functions leptin may have, the level of leptin will generally always be a good biomarker for the amount of body fat, which, as described above, is an important determinant of hypertension risk. In this context, it …

Markers of oxidative stress in obese men with and without hypertension

Abstract Objectives: The aim of our study was to investigate if the 24-hour excretion of the urinary markers for oxidative stress to DNA and RNA, measured as 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro-guanosine (8-oxoGuo), respectively, were increased in obese individuals with or without hypertension compared to lean controls. Methods: A total of 63 obese hypertensive men (obeseHT), 40 obese normotensive men (obeseNT) and 27 lean normotensive men (leanNT) were included in the study. Body mass index (BMI) was between 20.0 and 24.9 kg/m2 in leanNT participants and ≥30 kg/m2 in obese participants. Hypertension was defined as a mean 24-hour systolic ambulatory blood pressure (AMBP) ≥ 130 mmHg or a mean 24-hour diastolic AMBP ≥80 mmHg and normotension as mean 24-hour AMBP <130/80 mmHg. Twenty-four hour urinary 8-oxoGuo and 8-oxodG excretion (nmol/24 h) were measured by a validated liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS). Results: Urinary 8-oxoGuo excretion was (median and [interquartile range]) 30.8 [27.8–32.2] nmol/24 h in leanNT, 36.8 [31.3–40.2] nmol/24 h in obeseNT and 40.6 [31.7–48.5] nmol/24 h in obeseHT. The difference was statistically significant (p = .002) and post hoc tests showed a significant difference between leanNT and obeseHT (p = .001) as well as obeseNT (p = .002), whereas the two obese groups did not differ (p = .6). No statistically significant differences in 8-oxodG concentrations were observed between the three groups (p = .3). Conclusion: The measurement of urinary excretion of 8-oxoGuo suggests that obesity in men, but not hypertension, is associated with increased oxidative damage to RNA.

High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy

Aims To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). Methods and results In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow-up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low-density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP. Conclusions The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP. Trial registration NCT00092677.

Markers of Inflammation and Hemodynamic Measurements in Obesity: Copenhagen City Heart Study

BACKGROUND Low-grade chronic inflammation has been proposed to play a major role in the pathogenesis of hypertension. Low-grade chronic inflammation is also closely associated with obesity, an established causative factor in the development of hypertension. The purpose of this study was to investigate the relationship between two markers of inflammation, C-reactive protein (CRP) and fibrinogen, and blood pressure (BP) and other hemodynamic variables in obese subjects. METHODS From a large cardiovascular study based in the general population, we selected subjects with a body mass index (BMI) > or =30 kg/m2, free of major cardiovascular diseases, not taking BP-lowering or lipid-lowering drugs (n = 487; women = 51.1%; median (5th to 95th percentile) age = 62 years (36-80)). The cardiovascular study included measurements of traditional and new risk factors, including ankle brachial BP index, a measure of subclinical atherosclerosis. CRP was determined by a high-sensitive assay. RESULTS In partial Spearman rank correlation analysis, adjusted for age and sex, we found no significant relationships between either CRP or fibrinogen and systolic BP, diastolic BP, pulse pressure, or ankle brachial index (rho: -0.057 to 0.068; P > 0.13). However, fibrinogen and CRP were found to be significantly related to heart rate (rho: 0.127-0.169; P < 0.01). CONCLUSIONS In this study of generally healthy obese subjects from the general population, we found no significant relationships between markers of inflammation and systolic BP or diastolic BP, showing that obese subjects with higher levels of inflammatory markers do not have higher BP levels than their obese counterparts with lower levels of inflammatory markers.