Relationship Between Two Common Lipoprotein Lipase Variants and the Metabolic Syndrome and Its Individual Components.

BACKGROUND: Common lipoprotein lipase (LPL) variants are important determinants of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol (C) concentrations. High TG/low HDL-C tend to cluster with hypertension, glucose intolerance, and abdominal obesity and comprise the metabolic syndrome (MetS). The role of LPL variants as a cause of MetS is unclear. This study investigated the relationship between two common LPL variants and the presence of MetS and its individual components. METHODS: Cross-sectional study, including 2348 Danish women (50.7%) and men, age 41-72 years, without known cardiovascular disease. Carrier status for the two common LPL variants: 447Ter (low TG/high HDL-C) and 291Ser (high TG/low HDL-C) was determined. The prevalence of MetS according to the National Cholesterol Education Program criteria was 16.6%. RESULTS: Of the 2348 participants, 19.8% had the 447Ter variant and 4.9% had the 291Ser variant. Compared with the reference variant, the prevalence of MetS was lower in carriers of the 447Ter variant (11.2% vs. 17.9%, P < 0.001) but with no difference in carriers of the 291Ser variant (18.4% vs. 16.5%, P = 0.59). Adjusted for age, sex, smoking, physical activity, alcohol consumption, and highest sex-specific insulin quartile, the relative risk of MetS was 0.63 (95% confidence interval [CI] 0.45-0.89, P < 0.01) for carriers of the 447Ter variant and 1.20 (95% CI 0.70-2.03, P > 0.05) for carriers of the 291Ser variant. Both LPL variants were associated with high TG/low HDL-C (P < 0.01), but not with the MetS components waist circumference, hypertension, and glucose intolerance (P > 0.05). CONCLUSION: The two common LPL variants were associated with MetS through their effect on high TG/low HDL-C.

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.

Blood pressure variability predicts cardiovascular events independently of traditional cardiovascular risk factors and target organ damage: a LIFE substudy.

BACKGROUND: Assessment of antihypertensive treatment is normally based on the mean value of a number of blood pressure (BP) measurements. However, it is uncertain whether high in-treatment visit-to-visit BP variability may be harmful in hypertensive patients with left ventricular hypertrophy (LVH). METHODS: In 8505 patients randomized to losartan vs. atenolol-based treatment in the LIFE study, we tested whether BP variability assessed as SD and range for BP6-24 months measured at 6, 12, 18 and 24 months of treatment was associated with target organ damage (TOD) defined by LVH on ECG and urine albumin/creatinine ratio at 24 months, and predicted the composite endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction (MI) or stroke occurring after 24 months (CEP = 630 events). RESULTS: In multiple regression models adjusted for mean BP6-24 months and treatment allocation, neither high BP6-24 months SD nor wide range were related to TOD at 24 months, except for a weak association between Sokolow-Lyon voltage and DBP6-24 months SD and range (both ß = 0.04, P < 0.01). Independently of mean BP6-24 months, treatment allocation, TOD and baseline characteristics in Cox regression models, CEP after 24 months was associated with DBP6-24 months SD [hazard ratio per 1 mmHg increase1.04, 95% confidence interval (95% CI) 1.01-1.06, P = 0.005], range (hazard ratio 1.02, 95% CI 1.01-1.03, P = 0.004), SBP6-24 months SD (hazard ratio 1.01, 95% CI 0.99-1.02, P = 0.07) and range (hazard ratio 1.006, 95% CI 1.001-1.01, P = 0.04). Adjusted for the same factors, stroke was associated with DBP6-24 months SD (hazard ratio 1.06, 95% CI 1.02-1.10, P = 0.001), range (hazard ratio 1.03, 95% CI 1.01-1.04, P = 0.001), SBP6-24 months SD (hazard ratio 1.02, 95% CI 1.002-1.04, P = 0.04) and range (hazard ratio 1.008, 95% CI 1.001-1.02, P = 0.05), but MI was not. CONCLUSION: In LIFE patients, higher in-treatment BP6-24 months variability was independently of mean BP6-24 months associated with later CEP and stroke, but not with MI or TOD after 24 months.

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.

Impact of age and gender on the prevalence and prognostic importance of the metabolic syndrome and its components in Europeans. The MORGAM Prospective Cohort Project.

OBJECTIVE: To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). METHODS: Using 36 cohorts from the MORGAM-Project with baseline between 1982-1997, 69094 men and women aged 19-78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. RESULTS: The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19-39 years to 60-78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P=0.01/P=0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). CONCLUSION: In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

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.

Do other cardiovascular risk factors influence the impact of age on the association between blood pressure and mortality? The MORGAM Project.

OBJECTIVE: To investigate age-related shifts in the relative importance of SBP and DBP as predictors of cardiovascular mortality and all-cause mortality and whether these relations are influenced by other cardiovascular risk factors. METHODS: Using 42 cohorts from the MORGAM Project with baseline between 1982 and 1997, 85 772 apparently healthy Europeans and Australians aged 19-78 years were included. During 13.3 years of follow-up, 9.2% died (of whom 7.2% died due to stroke and 21.1% due to coronary heart disease, CHD). RESULTS: Mortality risk was analyzed using hazard ratios per 10-mmHg/5-mmHg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, SBP and DBP were analyzed separately for blood pressure (BP) values above and below a cut-point wherein mortality risk was the lowest. For the total population, significantly positive associations were found between stroke mortality and SBP [hazard ratio = 1.19 (1.13-1.25)] and DBP at least 78 mmHg [hazard ratio = 1.08 (1.02-1.14)], CHD mortality and SBP at least 116 mmHg [1.20 (1.16-1.24)], and all-cause mortality and SBP at least 120 mmHg [1.09 (1.08-1.11)] and DBP at least 82 mmHg [1.03 (1.02-1.05)]. BP values below the cut-points were inversely related to mortality risk. Taking into account the age × BP interaction, there was a gradual shift from DBP (19-26 years) to both DBP and SBP (27-62 years) and to SBP (63-78 years) as risk factors for stroke mortality and all-cause mortality, but not CHD mortality. The age at which the importance of SBP exceeded DBP was for stroke mortality influenced by sex, cholesterol, and country risk. CONCLUSION: Age-related shifts to the superiority of SBP exist for stroke mortality and all-cause mortality, and for stroke mortality was this shift influenced by other cardiovascular risk factors.

Impact of age on the importance of systolic and diastolic blood pressures for stroke risk: the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project.

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥ 71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥ 71 mm Hg (SBP/DBP ≥ 71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12-1.18/1.03-1.09]) and negatively with DBP <71 mm Hg (0.88[0.79-0.98]). The hazard ratio for DBP decreased with age (P<0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age × DBP interaction, both SBP and DBP ≥ 71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥ 71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP.