Feasibility and agreement of a novel combined echocardiographic method to measure global longitudinal strain and strain rate compared to speckle tracking and tissue Doppler imaging.

Background: Currently, two echocardiographic techniques are used to measure deformation: tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). Recently, a technique combining STE and TDI (on TDI overlay images) has become available, allowing derivation of STE/TDI results from a single acquisition/reading (combined-STE/combined-TDI). We tested the feasibility and agreement of this novel technique to measure left ventricular deformation in the general population compared to STE and TDI.Methods: We examined a subsample of 106 consecutive subjects of the Asklepios Study, a population-based random sample of male/female volunteers without overt clinical disease (mean age: 55.9 years). Left ventricular deformation measurements were assessed with transthoracic echocardiography using the combined method, STE and TDI.Results: Almost all deformation parameters significantly differed between all methods. Global systolic longitudinal strain (GS) and strain rate (GSRs) values measured by combined-TDI were significantly higher (GS -17.2% ± 3.0, GSRs -0.9 s-1 ± 0.2) compared to TDI (GS -21.1% ± 2.2, GSRs -1.3 s-1 ± 0.2). Measurements by combined-STE were significantly lower (GS -19.1% ± 2.9, GSRs -1.0 s-1 ± 0.2) compared to STE (GS -18.2% ± 3.0, GSRs -0.9 s-1 ± 0.1). Overall, the smallest differences and highest agreement were observed between STE and combined-STE (GS r = 0.84, p < .001; GSRs r = 0.70, p < .001).Conclusions: The comparison of methods showed different values and poor agreement between the echocardiographic modalities. Regrettably, the combined method does not make it possible to obtain in a single image/measurement results that are comparable to STE and TDI data in the general population.

Muscle strength is a major determinant of the blood pressure response to isometric stress testing: the Asklepios population study.

AIM: Maximal handgrip strength is a strong predictor of cardiovascular mortality in economically and socioculturally diverse countries, yet the main determinants of cardiovascular response to change in afterload during handgrip are not well known. We examined the blood pressure (BP) responses during submaximal handgrip (at 25% of grip strength) and the determinants of grip strength. METHODS: We studied 2215 participants from a population-based random sample without overt clinical disease (Asklepios Study; mean age 56.2 years). Handgrip testing was performed using a modified Jamar dynamometer with direct visual feedback. Simultaneously, a validated finger plethysmographic device measured continuous BP and heart rate. RESULTS: During handgrip, SBP and DBP rose by, respectively, 20 ±â€Š13 and 10 ±â€Š6 mmHg. These changes were normally distributed and consistently higher in men. The main independent determinants of mean arterial pressure response during handgrip were: grip strength (F = 191.4; P < 0.001), baseline pulse pressure (F = 32.0; P < 0.001), height (F = 16.4; P < 0.001) and age (F = 12.8; P < 0.001). Grip strength was associated with muscle mass, better metabolic health, but also with higher baseline DBP. There was a significant graded increase in maximum pressure achieved and in the magnitude of pressure change during handgrip with increasing BP categories (P for trend <0.001). CONCLUSION: The population BP response to handgrip is variable and its predominant determinant turned out to be grip strength itself, which should be accounted for in future analyses. Higher baseline BP, even within the normotensive range, acted as an independent and graded predictor of BP increase during handgrip.

On cross-sectional associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study.

BACKGROUND: Systemic telomere length has been associated with measures of diastolic function, vascular stiffness and left ventricular mass mainly in smaller, patient-specific settings and not in a general population. In this study we describe the applicability of these findings in a large, representative population. METHODS AND RESULTS: Peripheral blood leukocyte telomere length (PBL TL) was measured using telomere restriction fragment analysis in the young to middle-aged (>2500 volunteers, ∼35 to 55 years old) Asklepios study population, free from overt cardiovascular disease. Subjects underwent extensive echocardiographic, hemodynamic and biochemical phenotyping. After adjusting for relevant confounders (age, sex, systolic blood pressure, heart rate, body mass index and use of antihypertensive drugs) we found no associations between PBL TL and left ventricular mass index (P = 0.943), ejection fraction (P = 0.933), peak systolic septal annular motion (P = 0.238), pulse wave velocity (P = 0.971) or pulse pressure (P = 0.999). In contrast, our data showed positive associations between PBL TL and parameters of LV filling: the transmitral flow early (E) to late (A) velocity ratio (E/A-ratio; P<0.001), the ratio of early (e') to late (a') mitral annular velocities (e'/a'-ratio; P = 0.012) and isovolumic relaxation time (P = 0.015). Interestingly, these associations were stronger in women than in men and were driven by associations between PBL TL and the late diastolic components (A and a'). CONCLUSIONS: In a generally healthy, young to middle-aged population, PBL TL is not related to LV mass or systolic function, but might be associated with an altered LV filling pattern, especially in women.

Asymmetry in prevalence of femoral but not carotid atherosclerosis.

OBJECTIVE(S): Atherosclerotic disease is caused by a combination of systemic and local factors (e.g. geometry) affecting local flow conditions. In contrast to the carotid artery, at the iliac-femoral artery region, a large degree of bilateral asymmetry exists. Therefore, we aimed to determine the influence of body side on the prevalence of atherosclerosis (i.e. plaque and intima-media thickness; IMT) at the carotid and femoral arteries. METHODS: Data were used from the ASKLEPIOS study, including 2524 apparently healthy individuals with a mean age of 46 years (range 35-55 years). Echographic images were obtained bilaterally of the carotid and femoral arteries. A single observer approach was used for the acquisition and quantification of plaques and IMT. RESULTS: The carotid artery displays no significant left-right difference in IMT values nor plaque prevalence (right: 12.0 vs. left 13.3%; P = 0.18). In contrast, for the femoral artery, the IMT distribution at the right common femoral artery is more skewed (P90 right: 1.11 mm, left 1.01 mm; P < 0.001), which is mirrored by a significantly higher plaque prevalence (right: 21.9 vs. left: 15.7%; P < 0.001). CONCLUSION: In the present study, atherosclerotic lesions are more prevalent at the right than at the left femoral artery. This finding highlights the possible role of local arterial geometry in the development of atherosclerosis and underscores the importance of the choice of body side when assessing vascular health.

Arterial stiffness and influences of the metabolic syndrome: a cross-countries study.

Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in ≥3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components--even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus--in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV).

Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects.

BACKGROUND: We have previously shown that in healthy young men, a less favorable body composition is associated with higher free triiodothyronine (fT3) levels within the euthyroid range. Besides, a higher free-triiodothyronine-to-free-thyroxin (fT3-to-fT4) ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum thyrotropin (TSH), thyroid hormone levels, and the fT3-to-fT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. METHODS: Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios Study (35-55 years, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cutoff values or TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. RESULTS: fT3 and the fT3-to-fT4 ratio were positively related to body mass index (BMI), waist circumference, and components of metabolic syndrome, that is, triglycerides, systolic and diastolic blood pressure, and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas fT4 was negatively associated with BMI, waist circumference, and triglycerides (p<0.001). TSH related positively with total cholesterol levels (p<0.01), triglycerides, and systolic and diastolic blood pressure (p<0.001). The fT3-to-fT4 ratio was further positively associated with the adiposity-related inflammation markers interleukin-6 and high-sensitivity C-reactive protein and to pulse wave velocity. All associations were adjusted for sex, age, height, and smoking, and most associations persisted after additional adjustment for weight or waist circumference. CONCLUSION: In healthy euthyroid middle-aged men and women, higher fT3 levels, lower fT4 levels, and thus a higher fT3-to-fT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk.

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.

Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones.

BACKGROUND: Thyroid hormone (TH) action takes place intracellularly; therefore, transport across the plasma membrane by specific TH transporters, such as MCT8, MCT10 and OATP1C1, is necessary. Several single nucleotide polymorphisms (SNPs) in these genes were reported to be associated with TH concentrations; however, results have been inconsistent. METHODS: Six SNPs in TH transporter genes (rs5937843-G/T and rs6647476-T/C in MCT8, rs14399-C/A in MCT10, rs10444412-C/T, rs10770704-C/T and rs36010656-C/A in OATP1C1) were genotyped in 2 cohorts; one consisting of 2416 men and women aged 35-55 yrs (Asklepios), and the other of 941 men aged 25-45 yrs (Siblos), using KASPar technology. TSH, FT3, FT4 and total T3 were determined by immuno-electrochemiluminescence in both cohorts; in the second cohort additional determination of total T4 by electrochemiluminescence and of reverse T3 (rT3) and thyroid binding globulin (TBG) by radioimmunoassays was performed. RESULTS: The first SNP in MCT8 (rs5937843-G/T) was inversely associated with FT4 concentrations in men but not in women. In Siblos, this SNP showed also negative associations with TT4 and rT3; in men from Asklepios a trend for positive association with TSH was observed. The second SNP in MCT8 (rs6647476-T/C) was negatively associated with FT3 levels in men from the Siblos and the Asklepios cohort. In addition, an inverse association with TT3 levels in men from the Siblos was observed. Rs36010656 (C/A) in OATP1C1 was not in Hardy-Weinberg equilibrium and therefore excluded from further analyses. The other 2 SNPs in OATP1C1 (rs10444412-C/T and rs10770704-C/T) and the SNP in MCT10 (rs14399-C/A) were not related to TH levels in either cohort. CONCLUSION: Two SNPs in MCT8 were related to circulating thyroid hormone levels in men but not in women: the rs5937843 polymorphism (G/T) was inversely associated with FT4 levels and the rs6647476 (T/C) polymorphism related negatively to circulating FT3.

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.

Central pulse pressure and its hemodynamic determinants in middle-aged adults with impaired fasting glucose and diabetes: the Asklepios study.

OBJECTIVE: Pulse pressure (PP), a strong predictor of cardiovascular events in type 2 diabetes, is a composite measure affected by several hemodynamic factors. Little is known about the hemodynamic determinants of central PP in type 2 diabetes or whether abnormalities in central pulsatile hemodynamics are already present in individuals with impaired fasting glucose (IFG). In a population-based study, we aimed to compare central PP and its hemodynamic determinants among adults with normal fasting glucose (n = 1654), IFG (n = 240), and type 2 diabetes (n = 33). RESEARCH DESIGN AND METHODS: We measured carotid pressure, left ventricular outflow, aortic root diameter, carotid artery flow, and distension in order to measure various structural and hemodynamic arterial parameters. RESULTS: IFG was associated with a greater mean arterial pressure (MAP) but was not associated with intrinsic aortic stiffening or abnormal aortic pulsatile indices after adjustment for MAP. After adjustment for age, sex, and MAP, type 2 diabetes was associated with a higher aortic root characteristic impedance (Zc), aortic root elastance-thickness product (Eh), and aortic root pulse wave velocity (but not aortic root diameter), a greater carotid-femoral pulse wave velocity, and lower total arterial compliance and wave reflection magnitude. Carotid size, Zc, distensibility, or Eh did not significantly differ between the groups. CONCLUSIONS: Type 2 diabetes, but not IFG, is associated with greater large artery stiffness, without abnormalities in aortic root diameter or carotid stiffness. Subjects with type 2 diabetes demonstrate a decreased reflection magnitude, which may indicate an increased penetration of pulsatile energy to distal vascular beds.

Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women.

BACKGROUND: Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. METHODS: Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. RESULTS: Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27-4.2 µU/L) and in narrow TSH range (0.5-2.5 µU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. CONCLUSION: We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart.

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.