Susanne Rasmussen

Prognostic Value of Aortic Pulse Wave Velocity as Index of Arterial Stiffness in the General Population

Background— Few population studies addressed the prognostic significance of aortic pulse wave velocity (APWV) above and beyond other cardiovascular risk factors. Methods and Results— We studied a sex- and age-stratified random sample of 1678 Danes aged 40 to 70 years. We used Cox regression to investigate the prognostic value of APWV, office pulse pressure (PP), and 24-hour ambulatory PP while adjusting for mean arterial pressure (MAP) and other covariates. Over a median follow-up of 9.4 years, the incidence of fatal and nonfatal cardiovascular end points, cardiovascular mortality, and fatal and nonfatal coronary heart disease amounted to 154, 62, and 101 cases, respectively. We adjusted for sex, age, body mass index, MAP measured in the office (conventional PP and APWV) or by ambulatory monitoring (24-hour PP), smoking, and alcohol intake. With these adjustments, APWV maintained its prognostic significance in relation to each end point (P<0.05), whereas office and 24-hour PP lost their predictive value (P>0.19), except for office PP in relation to coronary heart disease (P=0.02). For each 1-SD increment in APWV (3.4 m/s), the risk of an event increased by 16% to 20%. In sensitivity analyses, APWV still predicted all cardiovascular events after standardization to a heart rate of 60 beats per minute, after adjustment for 24-hour MAP instead of office MAP, and/or after additional adjustment for the ratio of total to HDL serum cholesterol and diabetes mellitus at baseline. Conclusions— In a general Danish population, APWV predicted a composite of cardiovascular outcomes above and beyond traditional cardiovascular risk factors, including 24-hour MAP.

Ambulatory Blood Pressure and Mortality A Population-Based Study

The relationship between ambulatory blood pressure and mortality in a general Western population is unknown. Therefore, we conducted this prospective study of a random sample of 1700 Danish men and women, aged 41 to 72 years, without major cardiovascular diseases. At baseline, ambulatory blood pressure, office blood pressure, and other risk factors were recorded. After a mean period of 9.5 years, 174 had died: 63 were cardiovascular deaths. In multivariate proportional hazards models, adjusted for other risk factors of significance, the relative risk of cardiovascular mortality (95% confidence interval) associated with 10 mm Hg increments in systolic and 5 mm Hg increments in diastolic ambulatory blood pressure were 1.51 (1.28 to 1.77) and 1.43 (1.26 to 1.61). The corresponding figures for all cause mortality were 1.18 (1.06 to 1.31) and 1.18 (1.09 to 1.28). The relative risks of cardiovascular mortality were lower for office blood pressure, and office blood pressure did not predict all cause mortality. When ambulatory and office blood pressures were entered in the same multivariate models, only the ambulatory blood pressures were significant predictors of all cause mortality and cardiovascular mortality. The relationship between ambulatory blood pressures and risk of mortality was log-linear, with no indication of a threshold. The absolute risk of mortality was also dependent on age and smoking status, and an upper “acceptable” ambulatory blood pressure based on risk of mortality could only be defined when other risk factors were taken into account. In conclusion, ambulatory blood pressure provided prognostic information on mortality above and beyond that of office blood pressure.

N-Terminal Pro Brain Natriuretic Peptide Is Inversely Related to Metabolic Cardiovascular Risk Factors and the Metabolic Syndrome

We wanted to investigate the relationship of N-terminal pro brain natriuretic peptide (Nt-proBNP) to metabolic and hemodynamic cardiovascular (CV) risk factors in the general population. From a population-based sample of 2656 people 41, 51, 61, or 71 years of age, we selected 2070 patients without previous stroke or myocardial infarction who did not receive any CV, antidiabetic, or lipid-lowering treatment in 1993 to 1994. Traditional CV risk factors, 24-hour blood pressures, left ventricular (LV) mass, and ejection fraction by echocardiography, pulse wave velocity, urine albumin/creatinine ratio (UACR), and serum Nt-proBNP were measured in 1993 to 1994. The metabolic syndrome was defined in accordance with the definition of the European Group for the Study of Insulin Resistance (EGIR). Higher log(Nt-proBNP) was in multiple regression analysis related to female gender (&bgr;=−0.37), older age (&bgr;=0.32), higher clinic pulse pressure (&bgr;=0.20), lower serum total cholesterol (&bgr;=−0.15), lower LVEF (&bgr;=−0.08, all P<0.001), lower log(serum insulin) (&bgr;=−0.07), lower log(plasma glucose) (&bgr;=−0.06, both P<0.01, lower log(serum triglyceride) (&bgr;=−0.06), lower body mass index (&bgr;=−0.05); lower heart rate (&bgr;=−0.05), higher logUACR (&bgr;=0.04, all P<0.05) and higher log(LV mass index) (&bgr;=0.04, P=0.07), adjusted R2=0.35, P<0.001). The metabolic syndrome was associated with lower Nt-proBNP (35 pg/mL versus 48 pg/mL; P<0.001) and shifted the positive relationship between pulse pressure and Nt-proBNP to the right (ie, higher blood pressure for a given level of Nt-proBNP). The metabolic syndrome was associated with lower Nt-proBNP levels and shifted the positive relationship between Nt-proBNP and pulse pressure to the right, creating a possible link between the metabolic syndrome and hypertension.

Influence of gender on short- and long-term mortality after acute myocardial infarction

The aim of this study was to assess differences in short- and long-term mortality between male and female patients with acute myocardial infarction (AMI). The study population consisted of 6,676 consecutive patients admitted alive with an enzyme-confirmed AMI to 27 Danish hospitals from 1990 to 1992. Five patients were excluded because of missing information. Female patients (n = 2,170) were on average 5 years older than male patients (n = 4,501, p <0.001), had lower body mass index, and more often had diabetes, hypertension, and congestive heart failure. Left ventricular systolic function was the same for men and women. Women received thrombolytic therapy less often. The 1-year mortality for female patients was 28 +/- 1% and for men 21 +/- 1% (p <0.001). The unadjusted risk ratio associated with male gender in a proportional-hazards model was 0.76 (95% confidence intervals [CI] 0.70 to 0.83). Adjustment for age removed the importance of gender, and the risk ratio associated with male gender was 1.06 (95% CI 0.97 to 1.2, p = 0.2). An introduction of further variables in the model did not change this. Subdividing mortality into 6-day, 30-day, and late mortality demonstrated a significantly increased mortality in women in the short-term (6 and 30 days), with a risk ratio in men of 0.58 (95% CI 0.42 to 0.81) and 0.80 (95% CI 0.65 to 0.99), respectively. From day 30 onward there was an increased mortality in men with a risk ratio of 1.16 (95% CI 1.03 to 1.31, p = 0.01). Thus, women admitted alive to the hospital with an AMI have an increased long-term mortality that is explained by their older age. However, short-term mortality in women seems to increase independently of other risk factors, but is later followed by an increase in mortality in men.

Normal values for ambulatory blood pressure and differences between casual blood pressure and ambulatory blood pressure: results from a Danish population survey.

Objective To determine normal values for 24 h ambulatory blood pressure in a Danish population and to study the relationship to casual blood pressure. Study population A random sample of 2656 Danish men and women participated in a population survey. The participants were selected in age groups and were aged 41–42, 51–52, 61–62 or 71–72 years during the survey. Methods Casual blood pressure (standard mercury sphygmomanometer) and 24 h ambulatory blood pressure (Takeda TM-2421) were measured successfully in 2082 subjects. All subjects under antihypertensive treatment (247) were excluded, restricting the study population to 1835 participants. Results Casual and 24 h ambulatory blood pressure were correlated (P < 0.0001) in all age and sex groups. Casual systolic/diastolic blood pressures were 129.6 ± 17.8/82.6 ± 10.3 for men and 125.1 ± 18.2/79.7 ± 9.9 mmHg for women. Twenty-four-hour average blood pressures were 130.8 ± 14.2/75.3 ± 8.6 for men and 122.4 ± 14.9/69.6 ± 8.3 mmHg for women. A multivariate linear logistic regression model confirmed that a high casual blood pressure (odds ratios 11/7 for systolic/diastolic blood pressure; P = 0.001) was the major determinant of a lower ambulatory than casual blood pressure; age and sex were less important. Conclusion The relationship between casual blood pressure on the one hand and the difference in casual and 24 h ambulatory blood pressure on the other hand suggests that ambulatory blood pressure represents a regression towards the mean compared to casual blood pressure. Any definition of an upper normal level of 24 h ambulatory blood pressure that is derived from a correlation between casual and ambulatory measurements will be inaccurate, and must await long-term studies of the relationship between ambulatory blood pressure and subsequent cardiovascular events.

Seromic profiling of colorectal cancer patients with novel glycopeptide microarray

Cancer‐associated autoantibodies hold promise as sensitive biomarkers for early detection of cancer. Aberrant post‐translational variants of proteins are likely to induce autoantibodies, and changes in O‐linked glycosylation represent one of the most important cancer‐associated post‐translational modifications (PTMs). Short aberrant O‐glycans on proteins may introduce novel glycopeptide epitopes that can elicit autoantibodies because of lack of tolerance. Technical barriers, however, have hampered detection of such glycopeptide‐specific autoantibodies. Here, we have constructed an expanded glycopeptide array displaying a comprehensive library of glycopeptides and glycoproteins derived from a panel of human mucins (MUC1, MUC2, MUC4, MUC5AC, MUC6 and MUC7) known to have altered glycosylation and expression in cancer. Seromic profiling of patients with colorectal cancer identified cancer‐associated autoantibodies to a set of aberrant glycopeptides derived from MUC1 and MUC4. The cumulative sensitivity of the array analysis was 79% with a specificity of 92%. The most prevalent of the identified autoantibody targets were validated as authentic cancer immunogens by showing expression of the epitopes in cancer using novel monoclonal antibodies. Our study provides evidence for the value of glycopeptides and other PTM‐peptide arrays in diagnostic measures.

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

Thresholds for pulse wave velocity, urine albumin creatinine ratio and left ventricular mass index using SCORE, Framingham and ESH/ESC risk charts.

Aims: Markers of subclinical target organ damage (TOD) increase cardiovascular (CV) risk prediction beyond traditional risk factors. We wanted to establish thresholds for three markers of TOD based on absolute CV risk in different risk chart categories. Methods and results: In a cohort of 1968 healthy patients, we measured urine albumin creatine ratio (UACR), pulse wave velocity (PWV), left ventricular mass index (LVMI) and traditional risk factors. Patients were categorized according to Systemic Coronary Evaluation (SCORE), European Society of Hypertension/European Society of Cardiology (ESH/ESC) risk chart and Framingham risk score (FRS) and three corresponding endpoints were recorded: CV death (SCORE-endpoint), a composite of CV death and nonfatal myocardial infarction and stroke (ESH/ESC-endpoint), and a composite that also included hospital admissions for ischemic heart disease, heart failure, peripheral arterial disease and transient cerebral ischemic attack (FRS-endpoint). During a median follow of 12.8 years events totaled 81 SCORE-, 153 ESH/ESC-endpoints and 280 FRS-endpoints. Thresholds for UACR, PWV and LVMI are presented using 10-year risk threshold of more than 5% (SCORE-endpoint), more than 10%(ESH/ESC-endpoint) and more than 20%(FRS-endpoint), which indicated high risk and eligibility for primary prevention. As an example, the threshold was 0.83 mg/mmol, 13.7 m/s and 119 g/m2 for UACR, PWV and LVMI, respectively, for patients at moderate added risk according to ESH/ESC risk chart. Conclusion: Thresholds for UACR, PVW and LVMI based on absolute risk have primarily impact on risk stratification in patients with intermediate risk. The thresholds for PWV and LVMI in patients with moderate risk according to the ESH/ESC risk chart were similar to currently applied thresholds whereas the threshold for UACR was considerable lower than the threshold for microalbuminuria.

High-sensitivity C-reactive protein is only weakly related to cardiovascular damage after adjustment for traditional cardiovascular risk factors.

Background The independent prognostic value of high-sensitivity C-reactive protein (hsCRP) has been questioned, and consequently we decided to investigate whether hsCRP was associated with subclinical cardiovascular (CV) damage independently of traditional CV risk factors. Methods In a population-based sample of 2028 apparently healthy individuals without prior stroke or myocardial infarction not receiving any CV, anti-diabetic or lipid-lowering treatment, aged 41, 51, 61 or 71 years, we measured in 1993 serum hsCRP, traditional CV risk factors (lifestyle, metabolic and hemodynamic) and assessed subclinical CV damage [atherosclerotic plaques in the carotid arteries, pulse wave velocity (PWV), urine albumin/creatinine ratio (UACR), left ventricular (LV) mass and ejection fraction]. Results Adjusting for age and gender in multiple regression analyses, higher log(hsCRP) was associated with higher logPWV (β = 0.15) and log(left ventricular mass index) (LVMI) (β = 0.09, both P < 0.001), LV relative wall thickness (β = 0.07, P < 0.01), logUACR (β = 0.04, P = 0.06) and more atherosclerotic plaques (β = 0.06, P < 0.05). However, higher log(hsCRP) was only weakly associated with higher logPWV(β = 0.06, P < 0.05) and more atherosclerotic plaques (β = 0.04, P = 0.06) when adjusting for other significant CV risk factors, such as daily smoking (β = 0.18), female gender (β = −0.17), older age (β = 0.11), lower log(high density lipoprotein cholesterol) (β = −0.11, all P < 0.001); wider waist (β = 0.17), higher body mass index (β = 0.14), higher heart rate (β = 0.06, all P < 0.01); and higher log(plasma glucose) (β = 0.05, P < 0.05) (adj. R2 = 0.19, P < 0.001). Conclusion After adjustment for traditional CV risk factors hsCRP was only associated with PWV and atherosclerotic plaques, indicating a possible effect of low-grade inflammation on macrovascular damage. The close relationship between traditional CV risk factors and hsCRP suggested that hsCRP was an integrated CV risk marker early in the development of atherosclerosis.

Cardiovascular risk prediction by N-terminal pro brain natriuretic peptide and high sensitivity C-reactive protein is affected by age and sex.

Background Previous studies have shown that the urine albumin/creatinine ratio (UACR), high sensitivity C-reactive protein (hsCRP) and N-terminal pro brain natriuretic peptide (Nt-proBNP) predict cardiovascular events in a general population aged 41, 51, 61 or 71 years. This study investigated the impact of age and sex on their prognostic performance in a subgroup of 1994 apparently healthy individuals without diabetes, previous stroke or myocardial infarction, who did not receive any cardiovascular, antidiabetic or lipid-lowering medication. Methods In 1993–1994 we recorded cardiovascular risk factors, UACR, hsCRP and Nt-proBNP. The composite cardiovascular endpoint (CEP) of cardiovascular death and non-fatal stroke or myocardial infarction was assessed after 9.5 years. Results In Cox regression analyses predicting CEP, the effects of log(hsCRP) and log(Nt-proBNP) were modulated by sex (P < 0.05) and age (P < 0.05), respectively. The effect of logUACR was not significantly modulated by age or sex. Log(hsCRP)/SD did not predict CEP in women, but did predict CEP in 41 plus 51-year-old men [hazard ratio (HR) 1.71; 95% confidence interval, 1.1–2.6; P < 0.05] and 61 plus 71-year-old men (HR 1.64; 1.3–2.2; P < 0.001). Log(Nt-proBNP)/SD predicted CEP in 61 plus 71-year-old women (HR 1.74; 1.2–2.5; P < 0.01) and in 61 plus 71-year-old men (HR 1.58; 1.3–2.0; P < 0.001). Conclusion Elevated hsCRP, reflecting early atherosclerosis, predicted CEP even in 41 plus 51-year-old men. Elevated Nt-proBNP, reflecting subclinical cardiovascular damage, predicted CEP in 61 plus 71-year-old subjects. Elevated UACR, reflecting endothelial dysfunction as well as microvascular damage, predicted events independently of age and sex, but primarily in 61 plus 71-year-old subjects.