Tine W. Hansen

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.

Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'Establishing normal and reference values'

Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study.

BACKGROUND Few studies have formally compared the predictive value of the blood pressure at night over and beyond the daytime value. We investigated the prognostic significance of the ambulatory blood pressure during night and day and of the night-to-day blood pressure ratio. METHODS We did 24-h blood pressure monitoring in 7458 people (mean age 56.8 years [SD 13.9]) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We calculated multivariate-adjusted hazard ratios for daytime and night-time blood pressure and the systolic night-to-day ratio, while adjusting for cohort and cardiovascular risk factors. FINDINGS Median follow-up was 9.6 years (5th to 95th percentile 2.5-13.7). Adjusted for daytime blood pressure, night-time blood pressure predicted total (n=983; p<0.0001), cardiovascular (n=387; p<0.01), and non-cardiovascular (n=560; p<0.001) mortality. Conversely, adjusted for night-time blood pressure, daytime blood pressure predicted only non-cardiovascular mortality (p<0.05), with lower blood pressure levels being associated with increased risk. Both daytime and night-time blood pressure consistently predicted all cardiovascular events (n=943; p<0.05) and stroke (n=420; p<0.01). Adjusted for night-time blood pressure, daytime blood pressure lost prognostic significance only for cardiac events (n=525; p> or =0.07). Adjusted for the 24-h blood pressure, night-to-day ratio predicted mortality, but not fatal combined with non-fatal events. Antihypertensive drug treatment removed the significant association between cardiovascular events and the daytime blood pressure. Participants with systolic night-to-day ratio value of 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal (> or =0.80 to <0.90). INTERPRETATION In contrast to commonly held views, daytime blood pressure adjusted for night-time blood pressure predicts fatal combined with non-fatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. The increased mortality in patients with higher night-time than daytime blood pressure probably indicates reverse causality. Our findings support recording the ambulatory blood pressure during the whole day.

Predictive Role of the Nighttime Blood Pressure

Numerous studies addressed the predictive value of the nighttime blood pressure (BP) as captured by ambulatory monitoring. However, arbitrary cutoff limits in dichotomized analyses of continuous variables, data dredging across selected subgroups, extrapolation of cross-sectional studies to prospective outcomes, and lack of comprehensive adjustments for confounders make interpretation of the literature difficult. We reviewed prospective studies with total mortality or a composite cardiovascular end point as an outcome in relation to the level and the circadian profile of systolic BP. We analyzed studies in hypertensive patients (n = 23 856) separately from those in individuals randomly recruited from populations (n = 9641). We pooled summary statistics and individual subject data, respectively. In both patients and populations, in analyses in which nighttime BP was additionally adjusted for daytime BP and vice versa, nighttime BP was a stronger predictor than daytime BP. With adjustment for the 24-hour BP, both the night-to-day BP ratio and dipping status remained significant predictors of outcome but added little prognostic value over and beyond the 24-hour BP level. In the absence of conclusive evidence proving that nondipping is a reversible risk factor, the option whether or not to restore the diurnal blood pressure profile to a normal pattern should be left to the clinical judgment of doctors and should be individualized for each patient. Current guidelines on the interpretation of ambulatory BP recording need to be updated.

Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7030 individuals

Objective To investigate the multivariate-adjusted predictive value of systolic and diastolic blood pressures on conventional (CBP) and daytime (10–20 h) ambulatory (ABP) measurement. Methods We randomly recruited 7030 subjects (mean age 56.2 years; 44.8% women) from populations in Belgium, Denmark, Japan and Sweden. We constructed the International Database on Ambulatory blood pressure and Cardiovascular Outcomes. Results During follow-up (median = 9.5 years), 932 subjects died. Neither CBP nor ABP predicted total mortality, of which 60.9% was due to noncardiovascular causes. The incidence of fatal combined with nonfatal cardiovascular events amounted to 863 (228 deaths, 326 strokes and 309 cardiac events). In multivariate-adjusted continuous analyses, both CBP and ABP predicted cardiovascular, cerebrovascular, cardiac and coronary events. However, in fully-adjusted models, including both CBP and ABP, CBP lost its predictive value (P ≥ 0.052), whereas systolic and diastolic ABP retained their prognostic significance (P ≤ 0.007) with the exception of diastolic ABP as predictor of cardiac and coronary events (P ≥ 0.21). In adjusted categorical analyses, normotension was the referent group (CBP < 140/90 mmHg and ABP < 135/85 mmHg). Adjusted hazard ratios for all cardiovascular events were 1.22 [95% confidence interval (CI) = 0.96–1.53; P = 0.09] for white-coat hypertension (≥ 140/90 and < 135/85 mmHg); 1.62 (95% CI = 1.35–1.96; P < 0.0001) for masked hypertension (< 140/90 and ≥ 135/85 mmHg); and 1.80 (95% CI = 1.59–2.03; P < 0.0001) for sustained hypertension (≥ 140/90 and ≥ 135/85 mmHg). Conclusions ABP is superior to CBP in predicting cardiovascular events, but not total and noncardiovascular mortality. Cardiovascular risk gradually increases from normotension over white-coat and masked hypertension to sustained hypertension.

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.

Prognostic Value of Reading-to-Reading Blood Pressure Variability Over 24 Hours in 8938 Subjects From 11 Populations

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted (P≤0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: ≥1.07) with the exception of cardiac and coronary events (HR: ≤1.02; P≥0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted (P<0.05) total (HR: 1.11) and cardiovascular (HR: 1.16) mortality and all fatal combined with nonfatal end points (HR: ≥1.07), with the exception of cardiac and coronary events (HR: ≤1.03; P≥0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added <1% to the prediction of a cardiovascular event. Sensitivity analyses considering ethnicity, sex, age, previous cardiovascular disease, antihypertensive treatment, number of BP readings per recording, or the night:day BP ratio were confirmatory. In conclusion, in a large population cohort, which provided sufficient statistical power, BP variability assessed from 24-hour ambulatory recordings did not contribute much to risk stratification over and beyond 24-hour BP.

Diagnostic Thresholds for Ambulatory Blood Pressure Monitoring Based on 10-Year Cardiovascular Risk

Background— Current diagnostic thresholds for ambulatory blood pressure (ABP) mainly rely on statistical parameters derived from reference populations. We determined an outcome-driven reference frame for ABP measurement. Methods and Results— We performed 24-hour ABP monitoring in 5682 participants (mean age 59.0 years; 43.3% women) enrolled in prospective population studies in Copenhagen, Denmark; Noorderkempen, Belgium; Ohasama, Japan; and Uppsala, Sweden. In multivariate analyses, we determined ABP thresholds, which yielded 10-year cardiovascular risks similar to those associated with optimal (120/80 mm Hg), normal (130/85 mm Hg), and high (140/90 mm Hg) blood pressure on office measurement. Over 9.7 years (median), 814 cardiovascular end points occurred, including 377 strokes and 435 cardiac events. Systolic/diastolic thresholds for optimal ABP were 116.8/74.2 mm Hg for 24 hours, 121.6/78.9 mm Hg for daytime, and 100.9/65.3 mm Hg for nighttime. Corresponding thresholds for normal ABP were 123.9/76.8, 129.9/82.6, and 110.2/68.1 mm Hg, respectively, and those for ambulatory hypertension were 131.0/79.4, 138.2/86.4, and 119.5/70.8 mm Hg. After rounding, approximate thresholds for optimal ABP amounted to 115/75 mm Hg for 24 hours, 120/80 mm Hg for daytime, and 100/65 mm Hg for nighttime. Rounded thresholds for normal ABP were 125/75, 130/85, and 110/70 mm Hg, respectively, and those for ambulatory hypertension were 130/80, 140/85, and 120/70 mm Hg. Conclusions— Population-based outcome-driven thresholds for optimal and normal ABP are lower than those currently proposed by hypertension guidelines.

Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations

Background We and other investigators previously reported that isolated nocturnal hypertension on ambulatory measurement (INH) clustered with cardiovascular risk factors and was associated with intermediate target organ damage. We investigated whether INH might also predict hard cardiovascular endpoints. Methods and results We monitored blood pressure (BP) throughout the day and followed health outcomes in 8711 individuals randomly recruited from 10 populations (mean age 54.8 years, 47.0% women). Of these, 577 untreated individuals had INH (daytime BP <135/85 mmHg and night-time BP ≥120/70 mmHg) and 994 untreated individuals had isolated daytime hypertension on ambulatory measurement (IDH; daytime BP ≥135/85 mmHg and night-time BP <120/70 mmHg). During follow-up (median 10.7 years), 1284 deaths (501 cardiovascular) occurred and 1109 participants experienced a fatal or nonfatal cardiovascular event. In multivariable-adjusted analyses, compared with normotension (n = 3837), INH was associated with a higher risk of total mortality (hazard ratio 1.29, P = 0.045) and all cardiovascular events (hazard ratio 1.38, P = 0.037). IDH was associated with increases in all cardiovascular events (hazard ratio 1.46, P = 0.0019) and cardiac endpoints (hazard ratio 1.53, P = 0.0061). Of 577 patients with INH, 457 were normotensive (<140/90 mmHg) on office BP measurement. Hazard ratios associated with INH with additional adjustment for office BP were 1.31 (P = 0.039) and 1.38 (P = 0.044) for total mortality and all cardiovascular events, respectively. After exclusion of patients with office hypertension, these hazard ratios were 1.17 (P = 0.31) and 1.48 (P = 0.034). Conclusion INH predicts cardiovascular outcome in patients who are normotensive on office or on ambulatory daytime BP measurement.

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

Abstract.  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.