How to Measure Arterial Stiffness in Humans.

Despite the wide recognition of larger artery stiffness as a highly clinically relevant and independent prognostic biomarker, it has yet be incorporated into routine clinical practice and to take a more prominent position in clinical guidelines. An important reason may be the plethora of methods and devices claiming to measure arterial stiffness in humans. This brief review provides a concise overview of methods in use, indicating strengths and weaknesses. We classified and graded methods, highly weighing their scrutiny and purity in quantifying arterial stiffness, rather than focusing on their ease of application or the level at which methods have demonstrated their prognostic and diagnostic potential.

The Link Between Obstructive Sleep Apnea and Cardiovascular Disease.

Obstructive sleep apnea (OSA) is common in the general population and highly prevalent in patients with cardiovascular disease. In this paper, we review (1) the pathophysiological mechanisms of OSA that may causally contribute to cardiovascular disease; (2) current evidence regarding the association between OSA and hypertension, stroke, ischemic heart disease, heart failure, atrial fibrillation, and cardiovascular mortality; and (3) the impact of continuous positive airway pressure (CPAP) treatment on cardiovascular risk factors and outcomes. We emphasize the importance of obesity as a comorbidity of OSA and a confounder in the association between OSA and cardiovascular disease. We also discuss the importance of addressing obesity in patients with OSA, as a strategy to reduce the burden of cardiovascular risk factors in this population. Implications for the approach of patients' OSA in clinical practice and future research directions are discussed.

Associations between dietary inflammatory index and inflammatory markers in the Asklepios Study.

Previous research has shown that nutrients and certain food items influence inflammation. However, little is known about the associations between diet, as a whole, and inflammatory markers. In the present study, we examined the ability of a FFQ-derived dietary inflammatory index (DII) to predict inflammation. Data from a Belgian cross-sectional study of 2524 generally healthy subjects (age 35-55 years) were used. The DII is a population-based, literature-derived dietary index that was developed to predict inflammation and inflammation-related chronic diseases. The DII was calculated from FFQ-derived dietary information and tested against inflammatory markers, namely C-reactive protein (CRP), IL-6, homocysteine and fibrinogen. Analyses were performed using multivariable logistic regression, adjusting for energy, age, sex, BMI, smoking status, education level, use of non-steroidal anti-inflammatory drugs, blood pressure, use of oral contraceptives, anti-hypertensive therapy, lipid-lowering drugs and physical activity. Multivariable analyses showed significant positive associations between the DII and the inflammatory markers IL-6 (>1·6 pg/ml) (OR 1·19, 95 % CI 1·04, 1·36) and homocysteine (>15 µmol/l) (OR 1·56, 95 % CI 1·25, 1·94). No significant associations were observed between the DII and the inflammatory markers CRP and fibrinogen. These results reinforce the fact that diet, as a whole, plays an important role in modifying inflammation.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. METHODS: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. RESULTS: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; ßTOPCAT=0.539; P<0.0001; ßPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; ßTOPCAT=0.571; P<0.0001; ßPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. CONCLUSIONS: Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death. CONCLUSIONS: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

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.

Plant sterols and cardiovascular disease: a systematic review and meta-analysis.

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case-control, five nested case-control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.

Clusters of risk factors in metabolic syndrome and their influence on central blood pressure in a global study.

The effect of metabolic syndrome (MetS) and clusters of its components on central blood pressure (CBP) has not been well characterized. We aimed to describe the effect of MetS and clusters of its components on CBP in a large population and to identify whether this effect differs in men and women. We studied 15,609 volunteers (43% women) from 10 cohorts worldwide who participated in the Metabolic syndrome and Artery REsearch Consortium. MetS was defined according to the NCEP-ATP III criteria (GHTBW, glucose, high-density lipoprotein cholesterol, triglyceride, blood pressure, waist circumference). CBP was measured noninvasively and acquired from pulse wave analysis by applanation tonometry. MetS was associated with a 50% greater odds of having higher CSBP. After controlling for age, male sex, non HDL cholesterol, diabetes mellitus, and mean arterial pressure, only specific clusters of MetS components were associated with a higher CSBP; and some of them were significant in women but not in men. We identified "risky clusters" of MetS variables associated with high CSBP. Future studies are needed to confirm they identify subjects at high risk of accelerated arterial aging and, thus, need more intensive clinical management.

Longitudinal Changes of Input Impedance, Pulse Wave Velocity, and Wave Reflection in a Middle-Aged Population: The Asklepios Study.

[Figure: see text].

Sex differences in the association between arterial hypertension, blood pressure, and sleep apnea in the general population.

STUDY OBJECTIVES: To assess sex-related differences in the relationship between hypertension (HT), blood pressure (BP), and sleep apnea in the general population. METHODS: We performed home polygraphy in a cohort of 1809 men and women in the general population. Office BP was measured. Presence of HT (drug-treated, physician-diagnosed, or high BP during study visit) was also recorded. HT rate and BP were assessed over a range of 7 sleep apnea severity categories based on the respiratory event index (REI). RESULTS: The age-adjusted HT prevalence rate increased with higher REI in both sexes. After additional adjustment for obesity the association remained significant in women but not in men. In participants not treated with antihypertensive medications, age-adjusted BP increased with REI. Remarkably, the association was already significant within the normal range (REI < 5 events/h). The REI threshold for higher BP was situated at a distinctly lower cutoff point in women compared to men. After additional adjustment for obesity, the associations remained significant for diastolic but not systolic BP. CONCLUSIONS: Significant increases in the age-adjusted BP and HT rate in the general population were present at lower REI cutoffs in women compared to men. Even a very low number of respiratory events was associated with higher BP and HT prevalence. Adjustment for obesity attenuated these associations, especially in men. Sex differences in BP susceptibility across the sleep apnea spectrum may be present.

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.

Time-varying myocardial stress and systolic pressure-stress relationship: role in myocardial-arterial coupling in hypertension.

BACKGROUND: Myocardial afterload depends on left ventricular (LV) cavity size, pressure, and wall thickness, all of which change markedly throughout ejection. We assessed the relationship between instantaneous ejection-phase pressure and myocardial stress and the effect of arterial wave reflections on myocardial stress in hypertensive and normotensive adults. METHODS AND RESULTS: We studied 42 untreated hypertensive, 42 treated hypertensive, and 42 normotensive adults with normal LV ejection fraction. Time-resolved central pressure, flow, and LV geometry were measured with carotid tonometry, Doppler, and speckle-tracking echocardiography for computation of arterial load and time-varying circumferential and longitudinal myocardial stress. In all 3 groups, peak myocardial stress typically occurred in early systole (within the first 100 milliseconds of ejection), followed by a marked midsystolic shift in the pressure-stress relationship, which favored lower late systolic stress values (P<0.001) relative to pressure. The mean magnitude of this midsystolic shift was quantitatively important in all 3 groups (circumferential stress, 144 to 148 kdynes/cm(2)) and was independently predicted by a higher LV ejection fraction and ratio of LV end-diastolic cavity to wall volume. Time of peak myocardial stress independently correlated with time of the first systolic but not with time of the second systolic central pressure peak. CONCLUSIONS: Peak myocardial stress occurs in early systole, before important contributions of reflected waves to central pressure. In the presence of normal LV ejection fraction, a midsystolic shift in the pressure-stress relationship protects cardiomyocytes against excessive late systolic stress (despite pressure augmentation associated with wave reflections), a coupling mechanism that may be altered in various disease states.

Evaluation of standard and advanced preprocessing methods for the univariate analysis of blood serum 1H-NMR spectra.

Proton nuclear magnetic resonance ((1)H-NMR)-based metabolomics enables the high-resolution and high-throughput assessment of a broad spectrum of metabolites in biofluids. Despite the straightforward character of the experimental methodology, the analysis of spectral profiles is rather complex, particularly due to the requirement of numerous data preprocessing steps. Here, we evaluate how several of the most common preprocessing procedures affect the subsequent univariate analyses of blood serum spectra, with a particular focus on how the standard methods perform compared to more advanced examples. Carr-Purcell-Meiboom-Gill 1D (1)H spectra were obtained for 240 serum samples from healthy subjects of the Asklepios study. We studied the impact of different preprocessing steps--integral (standard method) and probabilistic quotient normalization; no, equidistant (standard), and adaptive-intelligent binning; mean (standard) and maximum bin intensity data summation--on the resonance intensities of three different types of metabolites: triglycerides, glucose, and creatinine. The effects were evaluated by correlating the differently preprocessed NMR data with the independently measured metabolite concentrations. The analyses revealed that the standard methods performed inferiorly and that a combination of probabilistic quotient normalization after adaptive-intelligent binning and maximum intensity variable definition yielded the best overall results (triglycerides, R = 0.98; glucose, R = 0.76; creatinine, R = 0.70). Therefore, at least in the case of serum metabolomics, these or equivalent methods should be preferred above the standard preprocessing methods, particularly for univariate analyses. Additional optimization of the normalization procedure might further improve the analyses.

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.

Impact of varying diastolic pressure fitting technique for the reservoir-wave model on wave intensity analysis.

The reservoir-wave model assumes that the measured arterial pressure is made of two components: reservoir and excess. The effect of the reservoir volume should be excluded to quantify the effects of forward and backward traveling waves on blood pressure. Whilst the validity of the reservoir-wave concept is still debated, there is no consensus on the best fitting method for the calculation of the reservoir pressure waveform. Therefore, the aim of this parametric study is to examine the effects of varying the fitting technique on the calculation of reservoir and excess components of pressure and velocity waveforms. Common carotid pressure and flow velocity were measured using applanation tonometry and doppler ultrasound, respectively, in 1037 healthy humans collected randomly from the Asklepios population, aged 35 to 55 years old. Different fitting techniques to the diastolic decay of the measured arterial pressure were used to determine the asymptotic pressure decay, which in turn was used to determine the reservoir pressure waveform. The corresponding wave speed was determined using the PU-loop method, and wave intensity parameters were calculated and compared. Different fitting methods resulted in significant changes in the shape of the reservoir pressure waveform; however, its peak and time integral remained constant in this study. Although peak and integral of excess pressure, velocity components and wave intensity changed significantly with changing the diastolic decay fitting method, wave speed was not substantially modified. We conclude that wave speed, peak reservoir pressure and its time integral are independent of the diastolic pressure decay fitting techniques examined in this study. Therefore, these parameters are considered more reliable diagnostic indicators than excess pressure and velocity which are more sensitive to fitting techniques.

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.

Allometric versus ratiometric normalization of left ventricular stroke volume by Doppler-echocardiography for outcome prediction in severe aortic stenosis with preserved ejection fraction.

BACKGROUND: Appropriate normalization methods to scale Doppler-derived stroke volume (SV) to body size in patients with aortic stenosis (AS) are poorly defined and reference values are lacking. We aim to establish reference values of normalized SV in adults, and to compare the prognostic value of SV normalized by different methods in AS patients. METHODS: In 2781 normotensive, non-obese adults without cardiovascular disease we defined normal relationships between SV and body size by nonlinear regression. Reference SV values were calculated by quantile regression. We subsequently analyzed by Cox analysis the prognostic performance of ratiometric and allometric normalized SV in 1450 patients with severe AS and preserved LVEF under medical and surgical management. RESULTS: Unlike ratiometric normalization, allometric indexation eliminated the residual relationships between normalized SV and body size. The allometric exponents that adequately described the SV-height (H) and SV-body surface area (BSA) relationships were 1.32, and respectively 0.88. In males, low-flow (LF) reference values were: <28 ml/m2, <30 ml/m, <30ml/(m2)0.88, and, respectively, <26 ml/m1.32, and in females <27 ml/m2, <28 ml/m, <29ml/(m2)0.88, and, respectively, <24 ml/m1.32. In patients with severe AS, SV/H1.32 was most consistently associated with mortality and showed better prognostic performance than other normalized SV parameters (adjusted hazard ratios: 1.86 for SV/H1.32, 1.72 for SV/H, 1.64 for SV/BSA, and 1.61 for SV/BSA0.88). Compared to H-normalization, BSA-normalization markedly overestimated the frequency of LF (3% vs. 9%). CONCLUSIONS: We provide normative reference values and appropriate normalization methods for SV by Doppler-echocardiography. In severe AS, SV/H1.32 seems the most appropriate indexation method, especially in obese individuals.

Sex-specific sleep apnea screening questionnaires: closing the performance gap in women.

BACKGROUND: The availability of poly(somno)graphy [P(S)G] for sleep apnea (SA) diagnosis is limited, making pre-test case evaluation an important challenge. The Neck, Obesity, Snoring, Age, Sex (NoSAS) and STOP-Bang (SBQ) scores are accepted screening tests, but their sex-specific performance in the general population is unknown. OBJECTIVE: To compare the sex-specific diagnostic characteristics of the NoSAS and SBQ scores, and to optimize the performance of these tools for men and women. METHODS: Participants from a population-based cohort (n = 2205) underwent clinical evaluation, including NoSAS, SBQ, and home polygraphy. RESULTS: We obtained successful polygraphy in 1809 participants. Moderate-to-severe SA was present in 11.7%. Diagnostic performance indices of NoSAS and the SBQ calculated on the overall group (men + women) overestimated the performance in both sexes separately. The sensitivity of NoSAS for an apnea/hypopnea index (AHI) ≥15 h-1 was acceptable in men (87.1%), but low in women (55.3%). The reverse was true for the specificity (39.9% in men, 87.4% in women). A similar sex-specific difference in diagnostic performance was seen with the SBQ. Using women-specific cut-offs for the scores (NoSAS ≥6 or SBQ ≥2) and neck circumference (>35 cm) increased the sensitivity in women to levels similar to men (88.5 and 87.2%). Although specificity decreased, it still remained higher than in men. CONCLUSION: In women, the sensitivity of NoSAS and the SBQ is too low for SA screening in the general population. Sex-specific cut-offs reverse this imbalance and achieve test sensitivities in women similar to those in men, whilst still retaining higher specificities than in men. Sleep questionnaires performance reporting should be sex-stratified.