Assessment of model based (input) impedance, pulse wave velocity, and wave reflection in the Asklepios Cohort

Objectives : Arterial stiffness and wave reflection parameters assessed from both invasive and non-invasive pressure and flow readings are used as surrogates for ventricular and vascular load. They have been reported to predict adverse cardiovascular events, but clinical assessment is laborious and may limit widespread use. This study aims to investigate measures of arterial stiffness and central hemodynamics provided by arterial tonometry alone and in combination with aortic root flows derived by echocardiography against surrogates derived by a mathematical pressure and flow model in a healthy middle-aged cohort. Methods : Measurements of carotid artery tonometry and echocardiography were performed on 2226 ASKLEPIOS study participants and parameters of systemic hemodynamics, arterial stiffness and wave reflection based on pressure and flow were measured. In a second step, the analysis was repeated but echocardiography derived flows were substituted by flows provided by a novel mathematical model. This was followed by a quantitative method comparison. Results : All investigated parameters showed a significant association between the methods. Overall agreement was acceptable for all parameters (mean differences: -0.0102 (0.033 SD) mmHg*s/ml for characteristic impedance, 0.36 (4.21 SD) mmHg for forward pressure amplitude, 2.26 (3.51 SD) mmHg for backward pressure amplitude and 0.717 (1.25 SD) m/s for pulse wave velocity). Conclusion : The results indicate that the use of model-based surrogates in a healthy middle aged cohort is feasible and deserves further attention

Evolocumab and clinical outcomes in patients with cardiovascular disease

BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approxi - mately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 pa - tients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for un - stable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confi - dence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for base - line LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (includ - ing new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with athero - sclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Assessing arterial distensibility using ultrasound wall-tracking diameter distension: an urgent need for direct stiffness measurement!

Background: Arterial stiffness is increasingly used as an early marker of atherosclerosis and for the individual's assessment of cardiovascular risk. Ultrasound wall tracking allows assessing the distensibility coefficient DC = (ΔD/D)/ΔP with D diastolic diameter, ΔD cyclic diameter change and ΔP the local pulse pressure. Although DC depends on intrinsic stiffness, it also depends on vessel geometry. In this study, we reconcile DC of the common carotid artery measured within the framework of the Asklepios population study. Methods: Diameter, intimamedia thickness (IMT) and DC of the left common carotid artery were assessed in 2315 (1191women) apparently healthy subjects (age 35-56), using vascular ultrasound (Vivid 7, 12L probe) and wall tracking (media-adventitia transition) techniques. Evolution of DC and IMT/D with age was evaluated within the context of a theoretical framework linking DC, IMT/D and the Young elasticity modulus E [DC =1/(2.E.IMT/D)]. Results DC was higher in women than in men for age (35-40), while the inverse was true at age (51-56), suggesting a more rapid increase in stiffness in women. This evolution in DC is partly explained by arterial remodelling (increase in IMT/D) accompanied by an increase in intrinsic stiffness. While DC decreases by >30%, our data suggest an increase in intrinsic stiffness of about 25% over the studied age range. Conclusions: Clinically used measures of arterial stiffness are intrinsically dependent on arterial geometry. Direct measurements of stiffness are highly needed to avoid the ambiguity between an artery's kinematic behavior and its intrinsic mechanical properties

Cost-effectiveness of rivaroxaban versus warfarin for stroke prevention in atrial fibrillation in the Belgian healthcare setting

Warfarin, an inexpensive drug that has been available for over half a century, has been the mainstay of anticoagulant therapy for stroke prevention in patients with atrial fibrillation (AF). Recently, rivaroxaban, a novel oral anticoagulant (NOAC) which offers some distinct advantages over warfarin, the standard of care in a world without NOACs, has been introduced and is now recommended by international guidelines. The aim of this study was to evaluate, from a Belgian healthcare payer perspective, the cost-effectiveness of rivaroxaban versus use of warfarin for the treatment of patients with non-valvular AF at moderate to high risk. A Markov model was designed and populated with local cost estimates, safety-on-treatment clinical results from the pivotal phase III ROCKET AF trial and utility values obtained from the literature. Rivaroxaban treatment was associated with fewer ischemic strokes and systemic embolisms (0.308 vs. 0.321 events), intracranial bleeds (0.048 vs. 0.063), and myocardial infarctions (0.082 vs. 0.095) per patient compared with warfarin. Over a lifetime time horizon, rivaroxaban led to a reduction of 0.042 life-threatening events per patient, and increases of 0.111 life-years and 0.094 quality-adjusted life-years (QALYs) versus warfarin treatment. This resulted in an incremental cost-effectiveness ratio of a,not sign8,809 per QALY or a,not sign7,493 per life-year gained. These results are based on valuated data from 2010. Sensitivity analysis indicated that these results were robust and that rivaroxaban is cost-effective compared with warfarin in 87 % of cases should a willingness-to-pay threshold of a,not sign35,000/QALY gained be considered. The present analysis suggests that rivaroxaban is a cost-effective alternative to warfarin therapy for the prevention of stroke in patients with AF in the Belgian healthcare setting

The Parametrized Diastolic Filling Formalism: Application in the Asklepios Population

peer reviewe

Amplitude of the forward Pf and backward Pb traveling pressure wave (A, B) and pulse wave velocity (C) as functions of sex and age.

<p>Q1, 35–40 years, 277/300 (m/w); Q2, 41–45 years, 274/303 (m/w); Q3, 46–50 years 265/281 (m/w); Q4, 51–56 years, 247/279 (m/w).</p

Changes in the shape of the modeled flow wave and the resulting stroke volume SV (ml) for a given heart rate HR and blood pressure level depending on arterial compliance Ca (ml/mmHg) and systemic vascular resistance SVR (mmHg*s/ml).

<p>Left: real scale, right: normalized to a height of 1 arbitrary unit (AU). Parameter values for A (Ca = 0.8, SVR = 1.0, SV = 99), B (Ca = 1.0, SVR = 1.4, SV = 71) and C (Ca = 1.2, SVR 1.8, SV = 55).</p