New risk markers for cardiovascular prevention.

The importance of total cardiovascular (CV) risk estimation before management decisions are taken is well established. Models have been developed that allow physicians to stratify the asymptomatic population in subgroups at low, moderate, high, and very high total CV risk. Most models are based on classical CV risk factors: age, gender, smoking, blood pressure, and lipid levels. The impact of additional risk factors is discussed here, looking separately at the predictive increments of novel biomarkers and of indicators of subclinical atherosclerotic disease. The contribution of biomarkers to the total CV risk estimation is generally modest, and their usage should be limited to subjects at intermediate total CV risk. Detection of subclinical vascular damage may improve total CV risk estimation in asymptomatic subjects who are close to a threshold that could affect management decisions and in whom the chances of re-classification in a different risk category are great. There is, however, an urgent need for trials in which the value of using total CV risk estimation models is tested.

Family history of cardiovascular disease and offspring echocardiographic left ventricular structure and function: the Asklepios Study.

BACKGROUND: Moderate to small heritability has been observed for left ventricular (LV) structure and function in genetic epidemiology and genomewide association studies. The aim of this study was to explore whether this would be mirrored in an independent association between LV structure and function and a family history (FH) of cardiovascular disease (CVD) in a large population of middle-aged adults. METHODS: Subjects enrolled in the Asklepios Study, a population-based sample of 2,524 male and female volunteers, aged 35 to 55 years, free of overt CVD at baseline, were studied. LV structure and function were assessed using transthoracic echocardiography (by a single sonographer). FH data spanning 4 generations were acquired using a questionnaire. RESULTS: In unadjusted analyses, only small effects of FH of CVD on LV structure (relative wall thickness, P = .042; interventricular septal thickness, P = .002; LV mass, P = .038; allometrically adjusted LV mass, P = .014) and diastolic function (mitral annular e', P = .02) were observed. After adjusting for the more adverse risk factor profile associated with FH, no significant associations persisted. These results did not appreciably change using a more extended definition of FH of CVD or FH of hypertension. CONCLUSIONS: A positive FH for CVD was associated with differences in offspring cardiac structure and function, largely mediated by (but not independent from) a more adverse risk profile in those subjects with positive FH.

Addition of a novel, protective family history category allows better profiling of cardiovascular risk and atherosclerotic burden in the general population. The Asklepios Study.

OBJECTIVES: Whereas the importance of family history (FH) is widely recognized in cardiovascular risk assessment, its full potential could be underutilized, when applied with its current simple guidelines-based definition (cFH): presence of premature cardiovascular disease (CVD) in a first-degree relative. We tested the added value of a new, extended family history definition (eFH), also taking into account later onset of disease, second-degree relatives and number of affected relatives, on profiling cardiovascular risk and atherosclerotic burden in the general population. DESIGN: Longitudinal population study. SETTING: Random, representative population sample from Erpe-Mere and Nieuwerkerken (Belgium, primary care). SUBJECTS: 2524 male/female volunteers, aged 35-55 years, free from overt CVD. MAIN OUTCOME MEASURES: Subjects were extensively phenotyped including presence of atherosclerosis (ultrasound) and a newly developed FH questionnaire (4 generations). RESULTS: Compared to cFH, eFH was superior in predicting an adverse risk profile (glycemic state, elevated blood pressure, lipid abnormalities, presence of metabolic syndrome components) and presence of atherosclerosis (all age & sex-adjusted p<0.05). Unlike cFH, eFH remained a significant predictor of subclinical atherosclerosis after adjusting for confounders. Most relations with eFH were not graded but showed clear informational breakpoints, with absence of CVD (including late onset) in any first-degree relative being a negative predictor of atherosclerosis, and a particularly interesting phenotype for further study. CONCLUSIONS: A novel, extended FH definition is superior to the conventional definition in profiling cardiovascular risk and atherosclerotic burden in the general population. There remain clear opportunities to refine and increase the performance and informational content of this simple, readily-available inexpensive tool.

No shorter telomeres in subjects with a family history of cardiovascular disease in the Asklepios study.

OBJECTIVE: Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population-representative Asklepios Study. METHODS AND RESULTS: Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (≈ 35-55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without. CONCLUSIONS: These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD.

Noninvasive assessment of central and peripheral arterial pressure (waveforms): implications of calibration methods.

OBJECTIVES: Noninvasive estimation of central blood pressure (BP) from radial artery pressure waveforms is increasingly applied. We investigated the impact of radial artery waveform calibration on central BP assessment and calculated pressure amplification, with focus on the one-third rule used to estimate mean arterial BP (MAP). METHODS: Pressure waveforms were noninvasively measured at the radial and carotid arteries in 1873 individuals (age 45.8+/-6.1 years). Radial and carotid artery waveforms were calibrated using brachial artery DBP and SBP, MAP estimated with the one-third rule and MAP estimated as brachial DBP along with 40% of brachial artery pulse pressure. RESULTS: Central SBP obtained via a transfer function was 123.5 +/- 15.7, 117.8 +/- 14.2 and 126.0 +/- 15.4 mmHg (mean +/- SD) following above-mentioned three calibration schemes, respectively. Using the same calibration schemes, carotid artery SBP was 131.4 +/- 15.2, 118.4 +/- 14.4 and 126.8 +/- 15.7 mmHg, respectively. Central-to-brachial amplification was 13.0 +/- 3.6 mmHg using second method as compared with 4.6 +/- 3.8 mmHg with third method. Brachial-to-radial amplification was actually negative (-6.3 +/- 4.5 mmHg) using second method, whereas 3.4 +/- 5.5 mmHg was found with third method. CONCLUSION: Both carotid artery SBP and central SBP obtained via a transfer function are highly sensitive to the calibration of the respective carotid artery and radial artery pressure waveforms. Our data suggest that the one-third rule to calculate MAP from brachial cuff BP should be avoided, especially when used to calibrate radial artery pressure waveforms for subsequent application of a pressure transfer function. Until more precise estimation methods become available, it is advisable to use 40% of brachial pulse pressure instead of 33% to assess MAP.

Systemic telomere length and preclinical atherosclerosis: the Asklepios Study.

AIMS: Peripheral blood leucocyte (PBL) telomere length (TL) is a systemic ageing biomarker and has been proposed to be an independent predictor of cardiovascular disease (CVD). We aimed at providing an explanation for this association by the evaluation of the biomarker value of PBL-TL in preclinical atherosclerosis. METHODS AND RESULTS: Peripheral blood leucocyte telomere length was assessed by telomere restriction fragment analysis in 2509 volunteers free from established CVD, aged approximately 35-55 years old, from the Asklepios Study cohort. Intima-media thickness (IMT) and plaque presence were determined by ultrasonography in both left and right carotid and femoral arteries. Peripheral blood leucocyte telomere length was not a significant independent determinant of IMT (P > 0.3) or plaque presence (P > 0.05), in either artery or either sex. In women but not in men, PBL-TL was a weak determinant of combined (carotid or femoral) plaque presence, adjusted for other risk factors (women: P = 0.03, men: P > 0.4). However, even in women presenting plaques, PBL-TL was still longer than in men. CONCLUSION: Since systemic TL is not a substantial underlying determinant of preclinical atherosclerosis, the association between CVD and TL cannot be explained by the fact that subjects with shorter inherited TL are predisposed to atherosclerosis.

Lower red blood cell counts in middle-aged subjects with shorter peripheral blood leukocyte telomere length.

Although telomere biology was revealed to play an important role in several hematopoietic disorders, its impact on the age-dependent dynamics of regular hematopoiesis is poorly understood. In vitro results suggest that particularly the erythropoietic capacity might be limited by critically short telomere length (TL). However, it remains unclear whether TL also affects erythropoiesis in healthy individuals in vivo. Therefore, we analyzed the associations between relevant hematopoietic parameters and peripheral blood leukocyte TL in the apparently healthy Asklepios study population, aged approximately 35-55 years (N > 2500). Our data indicate a clear positive, age and paternal age at birth adjusted, correlation between TL and red blood cell count, both in men (p < 0.001) and women (p = 0.011). This association was particularly significant in the older segment of the population (> 45 years old, both sexes: p = 0.003) and in younger men (p = 0.013), but not in younger women (p = 0.521). Further adjustment for known determinants in a general linear model revealed that peripheral blood leukocyte TL is most probably an independent predictor of red blood cell count (p < 0.001), suggesting that critical telomere shortening might also limit erythropoiesis in vivo. While negligible in a middle-aged population, the clinical consequences might be important in the elderly (e.g. in anemia of chronic disease). Further studies are required to confirm the impact of our results.

Oxidized low-density lipoprotein cholesterol is associated with decreases in cardiac function independent of vascular alterations.

In contrast to the plethora of vasculopathies to which oxidized low-density lipoprotein cholesterol (ox-LDL) can be linked, there are no data linking ox-LDL to myocardial (dys)function in the community. We tested whether ox-LDL, a marker of oxidative stress, was linked to early cardiac structural and functional damage in the general population. The Asklepios Study is a random sample of 2524 male and female volunteers, comparable to the Belgian population between 35 and 55 years free from overt cardiovascular disease. Cardiac morphology, systolic, and early and late diastolic tissue Doppler mitral annulus velocities were recorded during an echocardiography, followed by a vascular examination (carotid and femoral arteries). Serum ox-LDL was measured by sandwich ELISA using the mAb-4E6 monoclonal antibody. Effects of ox-LDL were assessed after adjustment for age, gender, lipid fractions, blood pressure, heart rate, height, weight, glycemia, smoking, and drug treatment. Mean ox-LDL was 96.0+/-38.9 U/L. After adjustment, increasing ox-LDL levels were associated with a more spherical left ventricular cavity (minor/major axis dimensions; P<0.001) and decreasing diastolic (early diastolic tissue Doppler mitral annulus velocity; P<0.001, more pronounced in women) and systolic function (amplitude of systolic tissue Doppler mitral annulus velocity; P=0.008, more pronounced in men). These results remained unaffected when further adjustments were made for inflammatory markers, lifestyle, or vascular damage (atherosclerosis and arterial stiffening). These results are the first "proof of concept" that ox-LDL impacts cardiac structure and function at a community level, independent of classic risk factors, lifestyle, inflammation, and prevalent vascular damage. Our data suggest that ox-LDL is a risk marker for early ventricular remodelling. However, the effect size in the general population is small.

Femoral plaques confound the association of circulating oxidized low-density lipoprotein with carotid atherosclerosis in a general population aged 35 to 55 years: the Asklepios Study.

OBJECTIVE: Reported associations of oxidized low-density lipoprotein (oxLDL) with noninvasive measures of atherosclerosis are inconsistent. In the Asklepios Study cohort of asymptomatic subjects aged 35 to 55 years, we evaluated the relationship of circulating oxLDL with subclinical atherosclerosis in the carotid and femoral arteries. METHODS AND RESULTS: Participants (n=2524, 51.5% females) completed a study questionnaire and underwent a clinical examination, blood analysis of oxLDL (mAb-4E6) and other risk markers, and ultrasound examination of intima-media thickness (IMT) and plaques in the left and right carotid and femoral arteries. oxLDL concentrations were highest in subjects with femoral plaques (n=658). In the group of subjects with carotid plaques (n=476), elevated oxLDL concentrations are related to concomitant femoral plaques detected in 54% of these subjects. Multivariate regression analyses (including anthropometric, hemodynamic, biochemical, and lifestyle variables) showed that femoral plaques are independently related to oxLDL whereas femoral IMT, carotid IMT, or carotid plaques were not independently associated with oxLDL. CONCLUSIONS: Circulating oxLDL is independently associated with femoral plaque and not with carotid artery wall damage.