Emerging pharmacological treatments to prevent abdominal aortic aneurysm growth and rupture

Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1 beta inhibition, anti-angiogenic agents and urocortins

Computer simulation of arterial blood flow

Computer models have been widely used to simulate pressure and flow propagation in the arterial system. While experimentation involving the human arterial system is difficult and impractical, computer models offer an attractive alternative for the study of arterial hemodynamics. The purpose of the present study was to develop a computer model of the whole systemic circulation and to use this model to study pressure and flow propagation under normal flow conditions, as well as under conditions of arterial disease;The mathematical model used to describe flow in an arterial segment was based on the one-dimensional continuity and momentum equations. The model includes nonlinearities arising from the convective acceleration term and the pressure-area relationship. The mathematical model also includes a seepage term for the modeling of small branches, as well as a body force term for the modeling of gravitational and external acceleration forces. Arterial segments that do not branch are terminated using modified windkessel lumped impedances. Arterial stenoses are modeled using an empirical pressure drop-flow relationship. The problem was solved numerically by employing either an explicit finite difference scheme, or a finite element scheme based on the Galerkin method;The physiological model consisted of 55 arterial segments and included most major arteries. The majority of the parameter data were obtained from the literature. Under normal flow conditions, the model predicted satisfactorily the major characteristics of pressure and flow throughout the arterial system. Tests were also run to assess the influence of model parameters, such as those related to boundary conditions, nonlinearities, and the wall shear stress model, on the model predictions;Finally, the model was used to study cases of medical interest, such as the effect of various forms of cardiovascular disease on pressure and flow waveforms. The cases studied include the effect of arterial stenoses on the mean flow and the pulsatility of the flow, the effect of heart valvular disease on central and peripheral pressure waveforms, as well as the effect of arteriosclerosis and hypertension on peripheral pressure pulse formation. The results were in reasonably good agreement with published experimental findings, suggesting that the computer model can be used to gain valuable information on the hemodynamics of the human arterial system

Systolic Hypertension Mechanisms: Effect of Global and Local Proximal Aorta Stiffening on Pulse Pressure

Decrease in arterial compliance leads to an increased pulse pressure, as explained by the Windkessel effect. Pressure waveform is the sum of a forward running and a backward running or reflected pressure wave. When the arterial system stiffens, as a result of aging or disease, both the forward and reflected waves are altered and contribute to a greater or lesser degree to the increase in aortic pulse pressure. Two mechanisms have been proposed in the literature to explain systolic hypertension upon arterial stiffening. The most popular one is based on the augmentation and earlier arrival of reflected waves. The second mechanism is based on the augmentation of the forward wave, as a result of an increase of the characteristic impedance of the proximal aorta. The aim of this study is to analyze the two aforementioned mechanisms using a 1-D model of the entire systemic arterial tree. A validated 1-D model of the systemic circulation, representative of a young healthy adult was used to simulate arterial pressure and flow under control conditions and in presence of arterial stiffening. To help elucidate the differences in the two mechanisms contributing to systolic hypertension, the arterial tree was stiffened either locally with compliance being reduced only in the region of the aortic arch, or globally, with a uniform decrease in compliance in all arterial segments. The pulse pressure increased by 58% when proximal aorta was stiffened and the compliance decreased by 43%. Same pulse pressure increase was achieved when compliance of the globally stiffened arterial tree decreased by 47%. In presence of local stiffening in the aortic arch, characteristic impedance increased to 0.10mmHgs/mL vs. 0.034mmHgs/mL in control and this led to a substantial increase (91%) in the amplitude of the forward wave, which attained 42mmHg vs. 22mmHg in control. Under global stiffening, the pulse pressure of the forward wave increased by 41% and the amplitude of the reflected wave by 83%. Reflected waves arrived earlier in systole, enhancing their contribution to systolic pressure. The effects of local vs. global loss of compliance of the arterial tree have been studied with the use of a 1-D model. Local stiffening in the proximal aorta increases systolic pressure mainly through the augmentation of the forward pressure wave, whereas global stiffening augments systolic pressure principally though the increase in wave reflections. The relative contribution of the two mechanisms depends on the topology of arterial stiffening and geometrical alterations taking place in aging or in diseas

Synchrotron-based visualization and segmentation of elastic lamellae in the mouse carotid artery during quasi-static pressure inflation

This dataset contains images that were obtained during quasi-static pressure inflation of mouse carotid arteries. Images were taken with phase propagation imaging at the X02DA TOMCAT beamline of the Swiss Light Source synchrotron at the Paul Scherrer Institute in Villigen, Switzerland. Scans of n=12 left carotid arteries (n-6 Apoe-deficient mice, n=6 wild-type mice, all on a C57Bl6J background) were taken at pressure levels of 0, 10, 20, 30, 40, 50, 70, 90 and 120 mmHg. For analysis we selected 75 images from the center of each stack (starting at the center of the stack, and skipping 2 of every three images in both cranial and caudal axial directions) for each sample and for each pressure level, resulting in a total of 75 x 12 x 9 = 8100 analyzed images from 108 different scans. Segmentation, 3D visualization and geometric analysis is presented in the corresponding manuscript. Files are uploaded in 16bit .tif format and are named: mouseid_pressurelevel_stacknumber, with mouseid consisting of either Apoe (Apoe-deficient) or Bl (wild-type) and the mouse number, pressurelevel varies from P0 to P120 and stacknumber indicates which image from the stack has been uploaded

On the Estimation of Total Arterial Compliance from Aortic Pulse Wave Velocity

Total arterial compliance (C T) is a main determinant of cardiac afterload, left ventricular function and arterio-ventricular coupling. C T is physiologically more relevant than regional aortic stiffness. However, direct, in vivo, non-invasive, measurement of C T is not feasible. Several methods for indirect C T estimation require simultaneous recording of aortic flow and pressure waves, limiting C T assessment in clinical practice. In contrast, aortic pulse wave velocity (aPWV) measurement, which is considered as the "gold standard” method to assess arterial stiffness, is noninvasive and relatively easy. Our aim was to establish the relation between aPWV and C T. In total, 1000 different hemodynamic cases were simulated, by altering heart rate, compliance, resistance and geometry using an accurate, distributed, nonlinear, one-dimensional model of the arterial tree. Based on Bramwell-Hill theory, the formula $$C_{\text{T}} = k \cdot {\text{aPWV}}^{ - 2}$$ was found to accurately estimate C T from aPWV. Coefficient k was determined both analytically and by fitting C T vs. aPWV data. C T estimation may provide an additional tool for cardiovascular risk (CV) assessment and better management of CV diseases. C T could have greater impact in assessing elderly population or subjects with elevated arterial stiffness, where aPWV seem to have limited prognostic value. Further clinical studies should be performed to validate the formula in viv

Quantification of the contribution of cardiac and arterial remodeling to hypertension.

The study aim was to quantify the individual and combined contributions of both the arterial system and the heart to systolic blood pressure in hypertension. We assessed the parameters of a heart-arterial model for normotensive control subjects and hypertensive patients with left ventricular adaptation patterns classified as normal, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy. The present simulations show that vascular stiffening alone increases the pulse pressure without increasing systolic blood pressure. It is only in combination with an increased peripheral resistance that arterial stiffening leads to systolic hypertension in concentric remodeling and concentric hypertrophy. The contribution of cardiac pump function to the increase in blood pressure depends on cardiac remodeling, hypertrophy, or both. In hypertensive patients with a normal left ventricle, the heart is responsible for 55% of the increase in systolic blood pressure. In concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, the cardiac contribution to the increase in systolic blood pressure is 21%, 65%, and 108%, respectively. We conclude that along with arterial changes, cardiac remodeling and hypertrophy contribute to hypertension