Jørgen Jeppesen

Relation of High TG–Low HDL Cholesterol and LDL Cholesterol to the Incidence of Ischemic Heart Disease An 8-Year Follow-up in the Copenhagen Male Study

High triglyceride (TG) and low HDL cholesterol (HDL-C) is the characteristic dyslipidemia seen in insulin-resistant subjects. We examined the role of this dyslipidemia as a risk factor of ischemic heart disease (IHD) compared with that of high LDL cholesterol (LDL-C) in the Copenhagen Male Study. In total 2910 white men, aged 53 to 74 years, free of cardiovascular disease at baseline, were subdivided into four groups on the basis of fasting concentrations of serum TG, HDL-C, and LDL-C. High TG-low HDL-C was defined as belonging to both the highest third of TG and the lowest third of HDL-C; this group encompassed one fifth of the population. High LDL-C was defined as belonging to the highest fifth of LDL-C. A control group was defined as not belonging to either of these two groups. Combined dyslipidemia was defined as belonging to both dyslipidemic groups. Age-adjusted incidence of IHD during 8 years of follow-up was 11.4% in high TG-low HDL-C, 8.2% in high LDL-C, 6.6% in the control group, and 17.5% in combined dyslipidemia. Compared with the control group, relative risks of IHD (95% confidence interval), adjusted for potentially confounding factors or covariates (age, body mass index, alcohol consumption, physical activity, non-insulin-dependent diabetes, hypertension, smoking, and social class), were 1.5 (1.0-2.1), P < .05; 1.3 (0.9-2.0), P = .16; and 2.4 (1.5-4.0), P < .01, in the three dyslipidemic groups, respectively. In conclusion, the present results showed that high TG-low HDL-C, the characteristic dyslipidemia seen in insulin-resistant subjects, was at least as powerful a predictor of IHD as isolated high LDL-C. The results suggest that efforts to prevent IHD should include intervention against high TG-low HDL-C, and not just against hypercholesterolemia.

Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population

Abstract.u2002 Eugen‐Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbæk S, Fenger M, Olsen MH, Hildebrandt PR, Borch‐Johnsen K, Jørgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308.

Relation between insulin and aortic stiffness: A population-based study

Recent studies have suggested that a high pulse wave velocity (PWV), a measure of aortic stiffness, may be a stronger risk factor for cardiovascular disease (CVD) than a high blood pressure (BP). The relation between insulin, believed to play an important role in the development and clinical course of high BP, and PWV is not yet clear. Therefore, we decided to examine the relationship between insulin and PWV in a large population-based study. The study population consisted of a random sample of 1213 women and 1207 men (age range, 41–72 years) without a history of myocardial infarction or stroke. Fasting insulin was determined together with conventional risk factors for CVD. PWV was recorded transcutaneously by a mechanical electrical principle with one transducer positioned over the left common carotid artery, and another over the left femoral artery. In univariate analysis, insulin was highly significantly related to PWV (standardized regression coefficient: 0.0669±0.0051; P<0.001). In multivariate analysis, controlling for all well-established predictors of PWV, such as age, systolic BP or mean BP and pulse pressure, sex, and heart rate, as well as controlling for conventional risk factors for CVD and use of BP-lowering drugs, the level of insulin remained a significant predictor of PWV (standardized regression coefficient: 0.0122±0.0048; P=0.012). In conclusion, the present study found that a higher insulin level was related to a higher PWV. This indicates that hyperinsulinaemia may affect BP and risk of CVD by increasing aortic stiffness.

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

Usefulness of soluble urokinase plasminogen activator receptor to predict repeat myocardial infarction and mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention.

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is an independent predictor of cardiovascular disease and all-cause mortality in healthy subjects. The prognostic capability of suPAR, its temporal course, and its relation to plasma C-reactive protein (CRP) in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention (PCI) is unknown. Therefore, the plasma suPAR and CRP levels were measured in 296 consecutive patients with ST-segment elevation myocardial infarction admitted for primary PCI at baseline and every 6 to 8 hours thereafter until the cardiac biomarker levels had peaked. The end points were all-cause mortality and fatal or nonfatal recurrent myocardial infarction (MI). During a median follow-up period of 5.75 years, 69 deaths and 48 nonfatal and 14 fatal recurrent MIs occurred. All-cause mortality increased significantly from 8.1% to 41.5% across increasing quartiles of suPAR levels at the end of follow-up (log-rank p <0.0001). After adjustment for other independent prognostic factors, a highly significant increase was seen in all-cause mortality (hazard ratio 1.45, 95% confidence interval, 1.19 to 1.76; p <0.001) and recurrent MI (hazard ratio 1.53, 95% confidence interval 1.16 to 2.01; p <0.01) for each standard deviation increment of suPAR levels). In contrast to plasma CRP, the suPAR levels remained stable after primary PCI. Furthermore, CRP did not predict mortality or reinfarction after adjustment for age and gender (p = 0.34). In conclusion, suPAR is a stable plasma biomarker after ST-segment elevation myocardial infarction treated with primary PCI that predicts all-cause mortality and recurrent MI.

Ambulatory Hypertension Subtypes and 24-Hour Systolic and Diastolic Blood Pressure as Distinct Outcome Predictors in 8341 Untreated People Recruited From 12 Populations

Background— Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce. Methods and Results— We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mmu2009Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs⩽1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P⩽0.0054). Isolated systolic hypertension (SBP24≥130 mmu2009Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P⩽0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR⩽0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P⩽0.0002) with a nonsignificant contribution of DBP24 (0.96⩽HR⩽1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P⩽0.043). Conclusions— The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.

Soluble Urokinase Plasminogen Activator Receptor for Risk Prediction in Patients Admitted with Acute Chest Pain

BACKGROUNDnPlasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict mortality in several clinical settings, but the long-term prognostic importance of suPAR in chest pain patients admitted on suspicion of non-ST-segment elevation acute coronary syndrome (NSTEACS) is uncertain.nnnMETHODSnsuPAR concentrations were measured on admission in 449 consecutive chest pain patients in a single center between January 3, 2005, and February 14, 2006. Patients were followed for all-cause mortality from discharge until July 28, 2011.nnnRESULTSnThe diagnoses at discharge comprised high-risk NSTEACS [non-ST elevation myocardial infarction or unstable angina with electrocardiogram (ECG) abnormalities] in 77 patients (17.2%) and low-risk NSTEACS without evidence of myocardial ischemia in 257 (57.2%) of patients. Another 115 (25.6%) of patients received other diagnoses. During a median follow-up of 5.7 years (range, 0.01-6.6 years) there were 162 (36.1%) deaths. suPAR was predictive of mortality independent of age, sex, smoking, final diagnosis for the hospitalization, comorbidities (diabetes, hypertension, previous myocardial infarction, and heart failure), and variables measured on the day of admission (renal function, inflammatory markers, and markers of myocardial ischemia) with a hazard ratio (95% CI) of 1.93 (1.48-2.51) per SD increase in log-transformed suPAR, P < 0.0001. The use of suPAR improved the predictive accuracy of abnormal ECG findings and increased troponin concentrations regarding all-cause mortality (c statistics, 0.751-0.805; P < 0.0001).nnnCONCLUSIONSnsuPAR is a strong predictor of adverse long-term outcomes and improves risk stratification beyond traditional risk variables in chest pain patients admitted with suspected NSTEACS.

Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension.

BackgroundSeveral attempts to decipher the genetics of hypertension of unknown causes have been made including large-scale genome-wide association analysis (GWA), but only a few genes have been identified. Unsolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition are the main reasons for the modest results. The level of the blood pressure is the consequence of the genotypic state of the presumably vast network of genes involved in regulating the vascular tonus and hence the blood pressure. Recently it has been suggested that components of the sphingolipid metabolism pathways may be of importance in vascular physiology. The basic metabolic network of sphingolipids has been established, but the influence of genetic variations on the blood pressure is not known. In the approach presented here the impact of genetic variations in the sphingolipid metabolism is elucidated by a two-step procedure. First, the physiological heterogeneity of the blood pressure is resolved by a latent class/structural equation modelling to obtain homogenous subpopulations. Second, the genetic effects of the sphingolipid metabolism with focus on de novo synthesis of ceramide are analysed. The model does not assume a particular genetic model, but assumes that genes operate in networks.ResultsThe stratification of the study population revealed that (at least) 14 distinct subpopulations are present with different propensity to develop hypertension. Main effects of genes in the de novo synthesis of ceramides were rare (0.14% of all possible). However, epistasis was highly significant and prevalent amounting to approximately 70% of all possible two-gene interactions. The phenotypic variance explained by the ceramide synthesis network were substantial in 4 of the subpopulations amounting to more than 50% in the subpopulation in which all subjects were hypertensive. Construction of the network using the epistatic values revealed that only 17% of the interactions detected were in the direct metabolic pathway, the remaining jumping one or more intermediates.ConclusionsThis study established the components of the ceramide/sphingosine-1-phosphate rheostat as central to blood pressure regulation. The results in addition confirm that epistasis is of paramount importance and is most conspicuous in the regulation of the rheostat network. Finally, it is shown that applying a simple case-control approach with single gene association analysis is bound to fail, short of identifying a few potential genes with small effects.

How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information

BACKGROUNDnAverage real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information.nnnMETHODSnARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results.nnnRESULTSnIn the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality.nnnCONCLUSIONSnForty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information.

Investigating the causal effect of vitamin D on serum adiponectin using a mendelian randomization approach

Background/Objectives:The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian randomization approach.Subjects/Methods:Serum 25-hydroxy vitamin D (25(OH)D) and serum total or high molecular weight (HMW) adiponectin were measured in two Danish population-based studies: the Inter99 study (6405 adults, 30–60 years) conducted in 1999–2001, and the MONICA10 study (2656 adults, 41–71 years) conducted in 1993–1994.Results:In the Inter99 study, serum 25(OH)D was positively associated with total adiponectin (the effect estimate in % per doubling of 25(OH)D was 4.78, 95% CI: 1.96, 7.68, P<0.001). Using variations in the vitamin D-binding protein gene and the filaggrin gene as instrumental variables, the causal effect in % was estimated to 61.46, 95% CI: 17.51, 120.28, P=0.003 higher adiponectin per doubling of 25(OH)D. In the MONICA10 cohort, no significant association was observed between the serum concentrations of 25(OH)D and HMW adiponectin (the effect estimate in % per doubling of 25(OH)D was −1.51, 95% CI: −5.80, 2.98, P=0.50), although the instrumental variables analysis to some extent supported a positive causal association (the effect estimate in % per doubling of 25(OH)D was 37.13, 95% CI: −3.67, 95.20, P=0.080).Conclusions:The results indicate a possible causal association between serum 25(OH)D and total adiponectin. However, the association was not replicated for HMW adiponectin. Thus, further studies are needed to confirm a causal relationship.