Sex- and age-related differences in the predictive capability of circulating biomarkers: from the MONICA 10 cohort.

OBJECTIVES: The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

Association between antecedent blood pressure, hypertension-mediated organ damage and cardiovascular outcome.

Purpose: The objective of this study was to test if combining antecedent systolic blood pressure (SBP) with traditional risk factors and hypertension-mediated organ damage (HMOD) improves risk stratification for subsequent cardiovascular disease.Materials and methods: 1910 subjects participated in this study. Antecedent SBP was defined as the average of measurements obtained in 1982 and in 1987. Current SBP was obtained in 1993. HMOD were examined in 1993. HMOD was defined as either atherosclerotic plaque(s), increased pulse wave velocity, increased urine albumin creatinine ratio (above the 90th percentile) or left ventricular hypertrophy. Major adverse cardiovascular events (MACE) including myocardial infarction, cerebrovascular disease, heart failure and arrhythmia were obtained from national registries.Results: Subjects were divided into two age categories: a middle-aged group (aged 41 or 51) and an older group (aged 61 or 71). From 1993 to 2010, 425 events were observed. In multivariable analysis with both current and antecedent SBP adjusted for traditional risk factors, current SBP was associated with each measure of HMOD whilst antecedent SBP was not significantly associated with urine albumin creatinine ratio in the older group, LVMI in the middle-aged group, or the presence of plaque in any of the age groups (all p > 0.15). When current and antecedent SBP were evaluated together, current SBP was not associated with MACE in the middle-aged subgroup [HR = 1.09 (0.96-1.22), p = 0.18] but remained associated with MACE in the older subgroup [HR = 1.21 (1.10-1.34), p < 0.01]. Contrariwise, antecedent SBP was only associated with MACE in the middle-aged subgroup [HR = 1.24 (1.04-1.48), p = 0.02]. Adding antecedent SBP to traditional risk factors did not improve the predictive accuracy of the survival model.Conclusion: In healthy non-medicated middle-aged subjects, antecedent SBP is associated with cardiovascular outcome independently of current BP, traditional risk factors and HMOD. However, improvement in risk stratification seems to be limited.

Impact of age on the association between 24-h ambulatory blood pressure measurements and target organ damage.

OBJECTIVE: The aim of this study was to evaluate the impact of age on the associations between hemodynamic components derived from 24-h ambulatory blood pressure (24-h ABPM) and target organ damage, in apparently healthy, nonmedicated individuals. METHODS: Twenty-four-hour ABPM and target organ damage (left ventricular mass index, pulse wave velocity, urine albumin : creatinine ratio and carotid atherosclerotic plaques) were evaluated in 1408 individuals. Associations were examined in regression models, stratified for age [middle-aged (41 or 51 years) or elderly (61 or 71 years)], and adjusted for sex, smoking status, and total-cholesterol. RESULTS: In middle-aged individuals, an increase of 10 mmHg in 24-h SBP was independently associated with an increase of 3.8 (2.7-4.8) g/m in LVMI. The effect was nearly doubled in the elderly subgroup, where the same increase resulted in an increase in LVMI of 6.3 (5.0-7.6) g/m (P for interaction <0.01). An increase of 10 mmHg of 24-h SBP was associated with a 6.7% increase in pulse wave velocity in middle-aged individuals and with an 9.1% increase in elderly individuals (P for interaction <0.01). An independent association between 24-h ABPM and urine albumin : creatinine ratio was only observed in the elderly subgroup. Associations between the presence of atherosclerotic plaques and components from 24-h ABPM except 24-h DBP were not modified by age (all P for interaction >0.26). CONCLUSION: Age enhances the associations between hemodynamic components obtained from 24-h ABPM and measures of arterial stiffness, microvascular damage, and cardiac structure, but not atherosclerosis.

Impact of Age and Target-Organ Damage on Prognostic Value of 24-Hour Ambulatory Blood Pressure.

Markers of target-organ damage and 24-hour ambulatory blood pressure (BP) measurement improve cardiovascular risk stratification. The prevalence of target-organ damage and raised BP increases with aging. The study aim was to evaluate the impact of age and target-organ damage on the prognostic value of ambulatory BP. Markers of target-organ damage and ambulatory BP were measured in 1408 healthy people aged 41 or 51 (middle-aged group), and 61 or 71 (older group) years. The primary outcome was cardiovascular events after 16 years of follow-up, with data obtained from national registries. The prognostic value of BP was evaluated with Cox regression models, adjusted for traditional risk factors and target-organ damage, including left ventricular mass, pulse wave velocity, carotid plaques, and urine albumin/creatinine ratio. A total of 323 events were observed. In comparison with traditional risk factors, adding systolic BP and presence of target-organ damage improved risk stratification by increasing concordance index from 0.711 to 0.728 (P=0.01). In middle-aged subjects with target-organ damage, increment in pulse pressure (hazard ratio, 1.70; 95% confidence interval, 1.31-2.21; P<0.01) and increment in average real variability (hazard ratio, 1.29; 95% confidence interval, 1.05-1.59; P=0.02) were associated with a greater risk of cardiovascular disease compared with subjects without target-organ damage: hazard ratio, 1.04 (95% confidence interval, 0.74-1.46; P=0.81); P for interaction, 0.02; and hazard ratio, 0.89 (95% confidence interval, 0.69-1.14; P=0.36); P for interaction, 0.01. Target-organ damage may be a marker of individual susceptibility to the harmful effects of pulse pressure and BP variability on the cardiovascular system in middle-aged individuals.

Elevated estimated arterial age is associated with metabolic syndrome and low-grade inflammation.

BACKGROUND: Arterial age can be estimated from equations relating arterial stiffness to age and blood pressure in large cohorts. We investigated whether estimated arterial age (eAA) was elevated in patients with the metabolic syndrome and/or known cardiovascular disease (CVD), which factors were associated with eAA and whether eAA added prognostic information. METHODS: In 1993, 2366 study participants, 41, 51, 61, and 71 years old, had traditional cardiovascular risk factors and carotid-femoral pulse wave velocity (cfPWV) measured. Risk groups were identified based on known CVD and components of metabolic syndrome, Systematic COronary Risk Evaluation, or Framingham risk score. From age, mean blood pressure, and cfPWV, eAA and estimated cfPWV (ePWV) were calculated. In 2006, the combined cardiovascular endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was registered. RESULTS: cfPWV and ePWV increased with ageing and cardiovascular risk (all P < 0.001), but ePWV increased more with ageing than cfPWV. The difference between eAA and chronological age was associated with male sex (ß = 0.14), higher heart rate (ß = 0.16 both P < 0.001), fasting glucose (ß = 0.08) soluble urokinase plasminogen activator receptor (ß = 0.06, both P < 0.01), and known CVD (ß = 0.06, P < 0.05) independently of age, SBP, and heart rate. Independently of Systematic COronary Risk Evaluation, eAA (hazard ratio = 1.20, P < 0.01) predicted CEP, but not as accurately as ePWV (hazard ratio = 1.58, P < 0.001) and cfPWV (hazard ratio = 1.32, P < 0.001) among apparently healthy study participants. CONCLUSION: Elevated eAA was associated with male sex, higher plasma glucose, and soluble urokinase plasminogen activator receptor and known CVD independently of age, SBP, and heart rate.

Estimated carotid-femoral pulse wave velocity has similar predictive value as measured carotid-femoral pulse wave velocity.

BACKGROUND: Carotid-femoral pulse wave velocity (cfPWV) adds significantly to traditional cardiovascular risk prediction, but is not widely available. Therefore, it would be helpful if cfPWV could be replaced by an estimated carotid-femoral pulse wave velocity (ePWV) using age and mean blood pressure, and previously published equations. The aim of this study was to investigate whether ePWV could predict cardiovascular events independently of traditional cardiovascular risk factors and/or cfPWV. METHOD: cfPWV was measured and ePWV was calculated in 2366 patients from four age groups of the Danish MONICA10 cohort. Additionally, the patients were divided into four cardiovascular risk groups based on Systematic COronary Risk Evaluation (SCORE) or Framingham risk score (FRS). In 2006, the combined cardiovascular endpoint of cardiovascular death, nonfatal myocardial infarction, stroke and hospitalization for ischemic heart disease was registered. RESULTS: Most results were retested in 1045 hypertensive patients from a Paris cohort. Bland-Altman plot demonstrated a relative difference of -0.3% [95% confidence interval (CI) -15 to 17%] between ePWV and cfPWV. In Cox regression models in apparently healthy patients, ePWV and cfPWV (per SD) added independently to SCORE in prediction of combined endpoint [hazard ratio (95%CI) = 1.38(1.09-1.76) and hazard ratio (95%CI) = 1.18(1.01-1.38)] and to FRS [hazard ratio (95%CI) = 1.33(1.06-1.66) and hazard ratio (95%CI) = 1.16(0.99-1.37)]. If healthy patients with ePWV and/or cfPWV at least 10 m/s were reclassified to a higher SCORE risk category, net reclassification index was 10.8%, P less than 0.01. These results were reproduced in the Paris cohort. CONCLUSION: ePWV predicted major cardiovascular events independently of SCORE, FRS and cfPWV indicating that these traditional risk scores have underestimated the complicated impact of age and blood pressure on arterial stiffness and cardiovascular risk.

Effective risk stratification in patients with moderate cardiovascular risk using albuminuria and atherosclerotic plaques in the carotid arteries.

OBJECTIVES: The aim of this study was to investigate whether subclinical vascular damage improved traditional risk prediction, reclassifying individuals with regard to primary prevention. METHODS: Two thousand and fifty-nine healthy individuals aged 41, 51, 61, and 71 years were divided into age, Systematic COronary Risk Evaluation (SCORE), and Framingham risk score (FRS) groups. Subclinical vascular damage was defined as carotid-femoral pulse wave velocity at least 12 m/s, and carotid atherosclerotic plaques or urine albumin/creatinine ratio (UACR) at least 90th percentile of 0.73/1.06 mg/mmol in men/women. The composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was recorded (n = 229). RESULTS: Both elevated UACR (P = 0.002) and atherosclerotic plaques (P < 0.0001) identified a subgroup of moderate SCORE risk patients and high-intermediate FRS risk patients with high risk (P = 0.04 and P = 0.001, respectively), whereas elevated carotid-femoral pulse wave velocity did not. Elevated UACR or presence of atherosclerotic plaques reclassified patients from moderate to high SCORE risk [net reclassification improvement of 6.4%; P = 0.025), or from high intermediate to high FRS risk (net reclassification improvement 8.8%; P = 0.002). Assuming primary prevention could reduce the relative cardiovascular risk by 24-27%, on the basis of actual levels of blood pressure and cholesterol, one composite endpoint could be avoided by giving primary prevention to 19 or 24 reclassified patients found by screening 52 or 104 patients with high-intermediate FRS or moderate SCORE risk, respectively. CONCLUSION: Elevated UACR and presence of atherosclerotic plaques could in a potentially cost-effective manner identify patients with moderate SCORE risk or high-intermediate FRS with actual high cardiovascular risk who will benefit from primary prevention.

Association between albuminuria, atherosclerotic plaques, elevated pulse wave velocity, age, risk category and prognosis in apparently healthy individuals.

METHOD: Two thousand and fifty-nine healthy individuals aged 41, 51, 61 and 71 years examined in 1993, were divided in age, SCORE and Framingham risk score (FRS) groups. Subclinical vascular damage (SVD) was defined as carotid-femoral pulse wave velocity (cfPWV) at least 12 m/s, carotid atherosclerotic plaques or albuminuria defined as urine albumin/creatinine ratio at least 90th percentile of 0.73/1.06 mg/mmol men/women. In 2006, the composite endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for ischemic heart disease was recorded (n = 229). RESULTS: With increasing age, SCORE or FRS risk group, prevalence of cfPWV at least 12 m/s (5.2, 14.5, 35.3, 53.5% or 4.4, 15.6, 50.9, 66.1% or 4.0, 9.5, 32.1, 56.1%), atherosclerotic plaque (4.0, 19.0, 35.3, 53.5% or 3.5, 16.8, 43.7, 55.9%, or 6.6, 7.6, 9.8, 20.0%) and albuminuria (7.9, 8.7, 11.4, 20.6% or 7.9, 8.2, 16.6, 19.5% or 6.6, 7.6, 9.8, 20.0%) increased, all P < 0.001.CEP was associated with albuminuria in individuals aged 61 or 71 years, with moderate or very high SCORE or intermediate or high FRS (all P < 0.05), with atherosclerotic plaques in individuals aged 41, 51 or 61 years, with moderate SCORE or with high-intermediate or high FRS (all P < 0.01), and with cfPWV at least 12 m/s in individuals aged 51 years (P < 0.001) or high FRS (P < 0.05). Presence of at least one SVD was significantly associated with an increased risk in individuals aged 51 [hazard ratio 2.7 (1.6-4.8)] and 61 years [hazard ratio 2.7 (1.5-4.7)], moderate [hazard ratio 2.4 (1.6-3.7)] or high SCORE risk group [hazard ratio 2.3 (1.2-4.7)] and low-intermediate [hazard ratio 3.3 (1.5-7.0)], high-intermediate [hazard ratio 2.3 (1.5-3.5)] and high FRS risk group [hazard ratio 2.0 (1.4-3.0)]. CONCLUSION: SVD and especially atherosclerotic plaques or urine albumin/creatinine ratio (UACR) at least 0.73/1.06 mg/mmol (men/women) added prognostic information in individuals aged 51 or 61 years or with moderate or intermediate risk.

Eligibility for renal denervation: experience at 11 European expert centers.

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure-lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center's criteria was 42.5% (95% confidence interval, 38.0%-47.0%) and 39.7% (36.2%-43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.