Margrét Leósdóttir

Telomeres and cardiovascular disease risk: an update 2013

Leukocyte telomere length (LTL) has been regarded as a potential marker of biologic aging because it usually shortens in a predictable way with age. Recently, a growing interest in cardiovascular aging has led to a number of new epidemiologic studies investigating LTL in various disease conditions. Some methodological problems exist because there are different methods available to determine LTL, and standardization is much needed. For example, in the majority of studies, patients with early-onset coronary heart disease have been shown to have shorter LTL. In addition, patients with diabetes mellitus complications tend to have shorter LTL than control subjects. On the other hand, increased left ventricular hypertrophy or mass is associated with longer LTL, and studies investigating hypertension have reported both shorter and longer LTL than found in normotensive control subjects. There is, therefore, a need for longitudinal studies to elucidate these complicated relationships further, to provide estimations of telomere attrition rates, and to overcome analytical problems when only cross-sectional studies are used. The understanding of cardiovascular aging and telomere biology may open up new avenues for interventions, such as stem cell therapy or agents that could retard this aging process over and beyond conventional risk factor control.

Dietary fat intake and early mortality patterns - data from The Malmö Diet and Cancer Study.

Objectives.  Most current dietary guidelines encourage limiting relative fat intake to <30% of total daily energy, with saturated and trans fatty acids contributing no more than 10%. We examined whether total fat intake, saturated fat, monounsaturated, or polyunsaturated fat intake are independent risk factors for prospective all‐cause, cardiovascular and cancer mortality.

Cardiovascular event risk in relation to dietary fat intake in middle-aged individuals: data from The Malmö Diet and Cancer Study

Background and design The hypothesis that diets rich in total and saturated fat and poor in unsaturated fats increase the risk for cardiovascular disease is still vividly debated. The aim of this study was to examine whether total fat, saturated fat, or unsaturated fat intakes are independent risk factors for cardiovascular events in a large population-based cohort. Methods 28098 middle-aged individuals (61% women) participated in the Malmö Diet and Cancer Study between 1991 and 1996. In this analysis, individuals with an earlier history of cardiovascular disease were excluded. With adjustments made for confounding by age and various anthropometric, social, dietary, and life-style factors, hazard ratios (HR) were estimated for individuals categorized by quartiles of fat intake [HR (95% confidence interval, CI), Coxs regression model]. Results No trend towards higher cardiovascular event risk for women or men with higher total or saturated fat intakes, was observed. Total fat: HR (95% CI) for fourth quartile was 0.98 (0.77-1.25) for women, 1.02 (0.84-1.23) for men; saturated fat: 0.98 (0.71-1.33) for women and 1.05 (0.83-1.34) for men. Inverse associations between unsaturated fat intake and cardiovascular event risk were not observed. Conclusions In relation to risks of cardiovascular events, our results do not suggest any benefit from a limited total or saturated fat intake, nor from relatively high intake of unsaturated fat. Eur J Cardiovasc Prev Rehabil 14:701-706

Relation between human vasopressin 1a gene variance, fat intake, and diabetes

BACKGROUND Male arginine vasopressin 1a receptor knockout mice (V1aR(-/-)) display a phenotype of low triglycerides and high glucose concentrations and high-fat-diet-induced obesity and diabetes. OBJECTIVE We investigated whether genetic variation of the human arginine vasopressin 1A (AVPR1A) gene is associated with phenotypic features resembling those of the V1aR(-/-) mouse. DESIGN In a population-based cross-sectional study in southern Sweden, middle-aged individuals (n = 6,055) were examined in 1991-1994. Associations between 4 AVPR1A tag single nucleotide polymorphisms (rs1042615, rs10784339, rs7308855, and rs10747983) and diabetes status, glucose and triglyceride concentrations, and BMI were analyzed. Furthermore, rs1042615 was related to diabetes status, glucose, and triglycerides within sex-specific quartiles of dietary fat intake (Q1(Fat)-Q4(Fat)) and BMI (Q1(BMI)-Q4(BMI)). RESULTS Subjects carrying the T allele of rs1042615 had lower concentrations of triglycerides than did CC carriers (1.36 +/- 0.77 compared with 1.42 +/- 0.89 mmol/L; P = 0.014), especially in nondiabetic subjects (P = 0.001). Carriers of the rs1042615 T allele had higher fasting blood glucose (5.20 +/- 1.44 mmol/L compared with 5.12 +/- 1.22 mmol/L; P = 0.036) and a tendency toward an increased prevalence of diabetes (odds ratio: 1.22; 95% CI: 0.99, 1.51; P = 0.067) compared with CC carriers. The less common rs10784339, rs7308855, and rs10747983 were not consistently associated with metabolic variables. Among men, the rs1042615 T allele was associated with diabetes exclusively within Q4(Fat) (odds ratio: 2.22; 95% CI: 1.05, 4.71; P = 0.04) and Q4(BMI) (odds ratio: 1.81; 95% CI: 1.11, 2.93; P = 0.02). CONCLUSION The rs1042615 T allele is associated with features resembling the phenotype of the V1aR(-/-) mouse, including uncoupling of the usual direct relation between glucose and triglycerides and an increased prevalence of diabetes in subjects with a high fat intake or who are overweight.

Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: A cross-sectional study

BACKGROUND Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts. METHODS We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 +/- 6 years) and the Malmö Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 +/- 6 years), evaluating associations with multivariable regression analysis. RESULTS In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (70-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c. CONCLUSIONS Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects.

The association between glucometabolic disturbances, traditional cardiovascular risk factors and self-rated health by age and gender: a cross-sectional analysis within the Malmo Preventive Project.

BackgroundThe increased risk of cardiovascular disease (CVD) in diabetic compared to non-diabetic subjects seems to decrease with age. Whether this age-related reduction applies to CVD risk factors, and whether it is limited to established diabetes mellitus (DM) or also applies to pre-diabetic conditions are not well known.MethodsUsing a cross-sectional design we compared the strength of the correlation between glucometabolic disturbances (by grouping), CVD risk factor burden and self-rated health, in two age groups: middle-aged (57-69 years) and older (70-86 years) subjects, (63% men), participating in the Malmö Preventive Project Re-examination Study (n = 18,238). Simple (unadjusted) logistic regression analysis was applied to estimate between-group differences and trends. Interaction analysis was applied to estimate differences between age groups.ResultsCVD risk factor burden and the proportion of subjects reporting poor self-rated health increased with increasing glucometabolic disturbance for men and women in both age groups (p-trend < 0.0001 for all). The slope of the trend curve with increasing CVD risk factor burden was significantly steeper for older women than for older men (p-interaction = 0.002). The slope of the trend curve for poor self-rated health was significantly steeper for middle-aged than for older men (p-interaction = 0.005), while no difference was observed between the age groups among women (p-interaction = 0.97).ConclusionsWe found no reduction in risk factor accumulation with increasing glucometabolic disturbance between middle-aged and older subjects. Our results indicate life-long CVD risk factor clustering with increased glucometabolic disturbance, and suggest that previously observed age-related reduction in excess CVD risk for subjects with DM might be due to a survival bias. However, our observations indicate more pronounced risk factor clustering and worse self-rated health with increased glucometabolic disturbance in older women than in older men.

Salt-inducible kinase 1 influences Na(+),K(+)-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure.

Objectives Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5′ adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na+,K+-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na+,K+-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation. Methods Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na+,K+-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype–phenotype association studies were performed in three Swedish and one Japanese population-based cohorts. Results SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change 15Gly→Ser in the SIK1 protein. SIK1-15Ser was found to increase plasma membrane Na+,K+-ATPase activity in cultured VSMC line from rat aorta. Genotype–phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for 15Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048). Conclusion The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.

The association between total energy intake and early mortality: data from the Malmö Diet and Cancer Study

Objectives.  In animal studies, low energy intake (EI) has been associated with a longer lifespan. We examine whether EI is an independent risk factor for prospective all‐cause mortality, cardiovascular and cancer mortality in humans.

Coronary flow velocity reserve reduction is comparable in patients with erectile dysfunction and in patients with impaired fasting glucose or well-regulated diabetes mellitus

Background There is growing evidence that erectile dysfunction is a sentinel for future coronary artery disease. Recently published studies have shown signs of impaired coronary endothelial function in patients with erectile dysfunction, without clinical cardiovascular disease and diabetes. We evaluated the magnitude of coronary vasodilatory dysfunction in men with erectile dysfunction, as compared with men with impaired glucose metabolism (impaired fasting glucose or diabetes) and healthy controls. Methods We investigated men aged 68–73 years with erectile dysfunction (n = 12), age-matched men with impaired glucose metabolism, who all proved to have erectile dysfunction (n = 15), and age-matched male controls (n = 12). Erectile dysfunction was evaluated using the International Index of Erectile Function (IIEF)-5 questionnaire. Coronary flow velocity reserve in the left anterior descending artery was examined using Doppler ultrasound and intravenous adenosine provocation. Results Coronary flow velocities at rest did not differ between the three groups, but maximum coronary flow velocity was significantly lower in the erectile dysfunction group (P = 0.004) and in the impaired glucose metabolism group (P = 0.019), as compared with controls. There was no difference between the erectile dysfunction and impaired glucose metabolism groups. Coronary flow velocity reserve was reduced in the erectile dysfunction group (P = 0.026) compared to controls, but was similar compared to the impaired glucose metabolism group. In multivariate analysis including all groups, erectile dysfunction score was the only independent predictor of reduced coronary flow velocity reserve (P = 0.020). Conclusions The magnitude of early coronary endothelial and smooth muscle cell dysfunction in otherwise healthy men with erectile dysfunction was comparable to that of patients with impaired glucose metabolism: a well known risk factor for coronary artery disease.

Follow-up duration influences the relative importance of OGTT and optimal timing of glucose measurements for predicting future type 2 diabetes

OBJECTIVE To examine the impact of follow-up duration on the incremental prognostic yield of a baseline oral glucose tolerance test (OGTT) for predicting type 2 diabetes and to assess the discrimination ability of blood glucose (BG) obtained at different time points during OGTT. DESIGN A prospective, population-based cohort study (Malmö Preventive Project) with inclusion of subjects from 1974 to 1992. METHODS A total of 5256 men without diabetes, who had BG measured at 0, 20, 40, 60, 90, and 120 min during OGTT (30 g/m2 glucose), were followed for 30 years. Incident type 2 diabetes was recorded using registries. The performance of OGTT added to a clinical prediction model (age, body mass index (BMI), diastolic blood pressure, fasting BG, triglycerides, and family history of diabetes) was assessed using Harrells concordance index (C-index) and integrated discrimination improvement (IDI). RESULTS Median age was 48 years, mean BMI 24.9 kg/m2, and mean fasting BG 4.7 mmol/L. Models with added post-load BG performed better than the clinical model (C-index: P = 0.08 for BG at 120 min at 5 years, otherwise P ≤ 0.045; IDI: P ≥ 0.06 for BG at 60 and 90 min at 5 years, otherwise P ≤ 0.01). With a longer follow-up duration, C-index decreased, and the C-index increase associated with OGTT was attenuated. Models including BG at 60 or 90 min performed significantly better than the model with BG at 120 min, evident beyond follow-up of 10 and 5 years, respectively. CONCLUSIONS OGTT provided incremental prognostic yield for type 2 diabetes prediction. BG measured at 60 or 90 min provided better discrimination than BG at 120 min.