Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.

BACKGROUND: Most people who begin statins abandon them, most commonly because of side effects. OBJECTIVES: The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. METHODS: Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the "nocebo" ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. RESULTS: A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. CONCLUSIONS: The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016).

Omega-3 index and blood pressure responses to eating foods naturally enriched with omega-3 polyunsaturated fatty acids: a randomized controlled trial.

Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor-1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world's population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (- 3.1 mmHg [- 5.8, - 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.

Automatic optic disc detection in colour fundus images by means of multispectral analysis and information content.

The optic disc (OD) in retinal fundus images is widely used as a reference in computer-based systems for the measurement of the severity of retinal disease. A number of algorithms have been published in the past 5 years to locate and measure the OD in digital fundus images. Our proposed algorithm, automatically: (i) uses the three channels (RGB) of the digital colour image to locate the region of interest (ROI) where the OD lies, (ii) measures the Shannon information content per channel in the ROI, to decide which channel is most appropriate for searching for the OD centre using the circular Hough transform. A series of evaluations were undertaken to test our hypothesis that using the three channels gives a better performance than a single channel. Three different databases were used for evaluation purposes with a total of 2,371 colour images giving a misdetection error of 3% in the localisation of the centre of the OD. We find that the area determined by our algorithm which assumes that the OD is circular, is similar to that found by other algorithms that detected the shape of the OD. Five metrics were measured for comparison with other recent studies. Combining the two databases where expert delineation of the OD is available (1,240 images), the average results for our multispectral algorithm are: TPR = 0.879, FPR = 0.003, Accuracy = 0.994, Overlap = 80.6% and Dice index = 0.878.

Evaluation of C-reactive protein before and on-treatment as a predictor of benefit of atorvastatin: a cohort analysis from the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm.

OBJECTIVES: The aim of this study was to determine whether baseline and on-statin C-reactive protein (CRP) are independent predictors of cardiovascular (CV) outcome beyond low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Use of CRP as a predictor of statin treatment remains controversial. METHODS: We investigated the relationship of baseline and on-treatment CRP with subsequent CV events in Cox models using a subset of white subjects with no history of CV disease from the UK ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). RESULTS: During 5.5 years of follow-up, a total of 488 subjects experienced a CV event. CV risk increased with baseline CRP (hazard ratio [HR] per 1 SD: 1.21; 95% confidence interval [CI]: 1.09 to 1.33) in an adjusted model. In ASCOT Lipid-Lowering Arm, the relative statin effect in preventing CV events did not differ according to tertiles of baseline CRP (p = 0.69). After 6 months of atorvastatin therapy, the median LDL-C and CRP were reduced by 38.7% and 25.8%, respectively. Those who achieved LDL-C below the median had a reduced CV risk (HR: 0.58; 95% CI: 0.34 to 0.97) compared with those who did not. In contrast, those who achieved a CRP level below the median did not have a reduced risk of CV events (HR: 0.95; 95% CI: 0.59 to 1.55). Among those who achieved LDL-C below the median, there was no difference in CV risk whether they also achieved a CRP level below (HR: 0.55; 95% CI: 0.30 to 1.02) or above the median (HR: 0.56; 95% CI: 0.30 to 1.03). CONCLUSIONS: In these primary prevention patients, although baseline CRP independently predicted CV event risk, the achieved CRP level on while statin therapy did not predict CV events, either alone or in combination with LDL-C.

Computational modeling of LDL and albumin transport in an in vivo CT image-based human right coronary artery.

Low wall shear stress (WSS) is implicated in endothelial dysfunction and atherogenesis. The accumulation of macromolecules is also considered as an important factor contributing to the development of atherosclerosis. In the present study, a fluid-wall single-layered model incorporated with shear-dependent transport parameters was used to investigate albumin and low-density lipoprotein (LDL) transport in an in vivo computed tomographic image-based human right coronary artery (RCA). In the fluid-wall model, the bulk blood flow was modeled by the Navier-Stokes equations, Darcy's law was employed to model the transmural flow in the arterial wall, mass balance of albumin and LDL was governed by the convection-diffusion mechanism with an additional reaction term in the wall, and the Kedem-Katchalsky equations were applied at the endothelium as the interface condition between the lumen and wall. Shear-dependent models for hydraulic conductivity and albumin permeability were derived from experimental data in literature to investigate the influence of WSS on macromolecular accumulation in the arterial wall. A previously developed so-called lumen-free time-averaged scheme was used to approximate macromolecular transport under pulsatile flow conditions. LDL and albumin accumulations in the subendothelial layer were found to be colocalized with low WSS. Two distinct mechanisms responsible for the localized accumulation were identified: one was insufficient efflux from the subendothelial layer to outer wall layers caused by a weaker transmural flow; the other was excessive influx to the subendothelial layer from the lumen caused by a higher permeability of the endothelium. The comparison between steady flow and pulsatile flow results showed that the dynamic behavior of the pulsatile flow could induce a wider and more diffuse macromolecular accumulation pattern through the nonlinear shear-dependent transport properties. Therefore, it is vital to consider blood pulsatility when modeling the shear-dependent macromolecular transport in large arteries. In the present study, LDL and albumin accumulations were observed in the low WSS regions of a human RCA using a fluid-wall mass transport model. It was also found that steady flow simulation could overestimate the magnitude and underestimate the area of accumulations. The association between low WSS and accumulation of macromolecules leading to atherosclerosis may be mediated through effects on transport properties and mass transport and is also influenced by flow pulsatility.

Influence of pulsatile flow on LDL transport in the arterial wall.

The accumulation of low-density lipoprotein (LDL) is one of the important factors in atherogenesis. Two different time scales may influence LDL transport in vivo: (1) LDL transport is coupled to blood flow with a pulse cycle of around 1 s in humans; (2) LDL transport within the arterial wall is mediated by transmural flow in the order of 10(-8) m/s. Most existing models have assumed steady flow conditions and overlooked the interactions between physical phenomena with different time scales. The objective of this study was to investigate the influence of pulsatile flow on LDL transport and examine the validity of steady flow assumption. The effect of pulsatile flow on transmural transport was incorporated by using a lumen-free cyclic (LFC) and a lumen-free time-averaged (LFTA) procedures. It is found that the steady flow simulation predicted a focal distribution in the post-stenotic region, differing from the diffuse distribution pattern produced by the pulsatile flow simulation. The LFTA procedure, in which time-averaged shear-dependent transport properties calculated from instantaneous wall shear stress (WSS) were used, predicted a similar distribution pattern to the LFC simulations. We conclude that the steady flow assumption is inadequate and instantaneous hemodynamic conditions have important influence on LDL transmural transport in arterial geometries with disturbed and complicated flow patterns.

Effects of transmural pressure and wall shear stress on LDL accumulation in the arterial wall: a numerical study using a multilayered model.

The accumulation of low-density lipoprotein (LDL) is recognized as one of the main contributors in atherogenesis. Mathematical models have been constructed to simulate mass transport in large arteries and the consequent lipid accumulation in the arterial wall. The objective of this study was to investigate the influences of wall shear stress and transmural pressure on LDL accumulation in the arterial wall by a multilayered, coupled lumen-wall model. The model employs the Navier-Stokes equations and Darcy's Law for fluid dynamics, convection-diffusion-reaction equations for mass balance, and Kedem-Katchalsky equations for interfacial coupling. To determine physiologically realistic model parameters, an optimization approach that searches optimal parameters based on experimental data was developed. Two sets of model parameters corresponding to different transmural pressures were found by the optimization approach using experimental data in the literature. Furthermore, a shear-dependent hydraulic conductivity relation reported previously was adopted. The integrated multilayered model was applied to an axisymmetric stenosis simulating an idealized, mildly stenosed coronary artery. The results show that low wall shear stress leads to focal LDL accumulation by weakening the convective clearance effect of transmural flow, whereas high transmural pressure, associated with hypertension, leads to global elevation of LDL concentration in the arterial wall by facilitating the passage of LDL through wall layers.

Fluid-wall modelling of mass transfer in an axisymmetric stenosis: effects of shear-dependent transport properties.

Mechanical forces, such as low wall shear stress (WSS), are implicated in endothelial dysfunction and atherogenesis. The accumulation of low density lipoprotein (LDL) and hypoxia are also considered as main contributing factors in the development of atherosclerosis. The objective of this study was to investigate the influences of WSS on arterial mass transport by modelling the flow of blood and solute transport in the lumen and arterial wall. The Navier-Stokes equations and Darcy's Law were used to describe the fluid dynamics of the blood in the lumen and wall respectively. Convection-diffusion-reaction equations were used to model LDL and oxygen transport. The coupling of fluid dynamics and solute dynamics at the endothelium was achieved by the Kedem-Katchalsky equations. A shear-dependent hydraulic conductivity relation extracted from experimental data in the literature was employed for the transport of LDL and a shear-dependent permeability was used for oxygen. The integrated fluid-wall model was implemented in Comsol Multiphysics 3.2 and applied to an axisymmetric stenosis. The results showed elevated LDL concentration and reduced oxygen concentration in the subendothelial layer of the arterial wall in areas where WSS is low, suggesting that low WSS might be responsible for lipid accumulation and hypoxia in the arterial wall.

Is carotid artery intima-media thickening a reliable marker of early atherosclerosis?

BACKGROUND: It is widely believed that carotid artery intima-media thickening represents an early marker for the development of atheroma. However, carotid intima-media thickening might also be expected to occur in response to an increased tensile stress and decreased wall shear stress which may accompany physical exercise. DESIGN, METHODS, AND RESULTS: In order to test this hypothesis 24 athletes (professional footballers) were compared to 14 age and sex matched control subjects. Each subject underwent carotid and femoral ultrasonography and echocardiography. The athletes had a greater left ventricular mass index compared with the controls: 135 (127-143) vs. 104 (91-116) g/m2, p < 0.001. In addition, they had a greater carotid intima-media thickness (IMT): 0.55 (0.52-0.57) vs. 0.51 (0.48-0.54) mm, p < 0.05. However, carotid artery diameters, femoral IMT and femoral artery diameters were similar: 6.0 (5.9-6.2) vs. 5.8 (5.6-6.1) mm, 0.43 (0.42-0.45) vs. 0.43 (0.41-0.45) mm and 8.3 (8.0-8.6) vs. 8.4 (8.0-8.7) mm, respectively. CONCLUSIONS: The increased carotid IMT of the athletes may result from intermittent exposure to markedly elevated systemic arterial pressures during exercise, resulting in intermittent elevations in carotid wall tensile stress. The lack of a disparity between athletes and controls for femoral IMT may be explained by the intermittent elevation of femoral wall tensile stress being accompanied by increased femoral artery blood flow and wall shear stress, which would tend to reduce any wall thickening. This is an important observation, since it suggests that an increased carotid IMT cannot be relied on solely as a marker of early atherosclerosis.

Measurement of hemodynamics in human carotid artery using ultrasound and computational fluid dynamics.

The objective of the study was to investigate the feasibility of using computational fluid dynamic modeling (CFD) with noninvasive ultrasound measurements to determine time-variant three-dimensional (3D) carotid arterial hemodynamics in humans in vivo. The effects of hyperoxia and hypoxic hypercapnia on carotid artery local hemodynamics were examined by use of this approach. Six normotensive volunteers followed a double-blind randomized crossover design. Blood pressure, heart rate, and carotid blood flow were measured while subjects breathed normal air, a mixture of 5% CO(2) and 15% O(2) (hypoxic hypercapnia), and 100% O(2) (hyperoxia). Carotid artery geometry was reconstructed on the basis of B-mode ultrasound images by using purpose-built image processing software. Time-variant 3D carotid hemodynamics were estimated by using finite volume-based CFD. Systemic blood pressure was not significantly affected by hyperoxia or hypoxic hypercapnia, but heart rate decreased significantly with hyperoxia. There was an increase in diastolic flow velocity in the external carotid artery after hypoxic hypercapnia, but otherwise carotid blood flow velocities did not change significantly. Compared with normal air, hyperoxic conditions were associated with a decrease in the width of the region of flow separation in the external carotid artery. During hyperoxia, there was also an increase in the minimum and a decrease in maximum shear stress in the bifurcation and hence a reduction in cyclic variation in shear stress. Hypoxic hypercapnia was associated with a reduced duration of flow separation in the external carotid artery and an increase in the minimum shear stress without affecting the cyclic variation in shear stress. This study demonstrates the feasibility of using noninvasive ultrasound techniques in conjunction with CFD to describe time-variant 3D hemodynamics in the human carotid arterial bifurcation in vivo.