A new approach for the evaluation of the severity of coarctation of the aorta using Doppler velocity index and effective orifice area: in vitro validation and clinical implications

Early detection and accurate estimation of COA severity are the most important predictors of successful long-term outcome. However, current clinical parameters used for the evaluation of the severity of COA have several limitations and are flow dependent. The objectives of this study are to evaluate the limitations of current existing parameters for the evaluation of the severity of coarctation of the aorta (COA) and suggest two new parameters: COA Doppler velocity index and COA effective orifice area. Three different severities of COAs were tested in a mock flow circulation model under various flow conditions and in the presence of normal and stenotic aortic valves. Catheter trans-COA pressure gradients and Doppler echocardiographic trans-COA pressure gradients were evaluated. COA Doppler velocity index was defined as the ratio of pre-COA to post-COA peak velocities measured by Doppler echocardiography. COA Doppler effective orifice area was determined using continuity equation. The results show that peak-to-peak trans-COA pressure gradient significantly increased with flow rate (from 83% to 85%). Peak Doppler pressure gradient also significantly increased with flow rate (80-85%). A stenotic or bicuspid aortic valve increased peak Doppler pressure gradient by 20-50% for a COA severity of 75%. Both COA Doppler velocity index and COA effective orifice area did not demonstrate significant flow dependence or dependence upon aortic valve condition. As a conclusion, COA Doppler velocity index and COA effective orifice area are flow independent and do not depend on aortic valve conditions. They can, then, more accurately predict the severity of COA.     

Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest

Central aortic pressure gives better insight into ventriculo-arterial coupling and better prognosis of cardiovascular complications than peripheral pressures. Therefore transfer functions (TF), reconstructing aortic pressure from peripheral pressures, are of great interest. Generalized TFs (GTF) give useful results, especially in larger study populations, but detailed information on aortic pressure might be improved by individualization of the TF. We found earlier that the time delay, representing the travel time of the pressure wave between measurement site and aorta is the main determinant of the TF. Therefore, we hypothesized that the TF might be individualized (ITF) using this time delay. In a group of 50 patients at rest, aged 28-66 yr (43 men), undergoing diagnostic angiography, ascending aortic pressure was 119 +/- 20/70 +/- 9 mmHg (systolic/diastolic). Brachial pressure, almost simultaneously measured using catheter pullback, was 131 +/- 18/67 +/- 9 mmHg. We obtained brachial-to-aorta ITFs using time delays optimized for the individual and a GTF using averaged delay. With the use of ITFs, reconstructed aortic pressure was 121 +/- 19/69 +/- 9 mmHg and the root mean square error (RMSE), as measure of difference in wave shape, was 4.1 +/- 2.0 mmHg. With the use of the GTF, reconstructed pressure was 122 +/- 19/69 +/- 9 mmHg and RMSE 4.4 +/- 2.0 mmHg. The augmentation index (AI) of the measured aortic pressure was 26 +/- 13%, and with ITF and GTF the AIs were 28 +/- 12% and 30 +/- 11%, respectively. Details of the wave shape were reproduced slightly better with ITF but not significantly, thus individualization of pressure transfer is not effective in resting patients.     

Direct correlation between calcium content and blood pressure: a study of aortic coarctation in rats

The calcium content of aorta was measured by atomic absorption after coarctation in the rat. At 7 and 14 days, the calcium content was elevated on the proximal side of the coarctation, where pressure was increased significantly. On the distal, low pressure side of the aortic coarctation, calcium was reduced significantly. There is a direct correlation between the blood pressure and the content of calcium (r = 0.69, P less than 0.001). The width of the aortic media on the high pressure side was increased significantly at 7 and 14 days after coarctation, whereas no significant changes in width were present on the low pressure side of the constriction. We conclude that pressure regulates the aortic calcium content, likely acting through a local effect.     

Baroreceptor influence on a spinal cardiovascular reflex

A stretch of the walls of the thoracic aorta, performed in vagotomized cats without obstructing aortic flow, induces increases in heart rate, myocardial contractility, and arterial pressure. These reflex responses are still present after high spinal section. Cats under chloralose-urethane anesthesia were vagotomized and one carotid sinus was isolated and perfused with arterial blood at constant flow. The contralateral carotid sinus nerve and both aortic nerves were sectioned. A stretch of the walls of the thoracic aorta between the 7th and 10th intercostal arteries induced a reflex increase in mean arterial pressure 29 +/- 2 mmHg (mean +/- SE). Stepwise increases of carotid sinus pressure (CSP) or electrical stimulation of the carotid sinus nerve induced stepwise decreases of this reflex response. At maximal baroreceptor stimulation (CSP 212 +/- 9 mmHg) the reflex response to aortic stretch was reduced by 42%. These experiments show that this spinal cardiovascular reflex is at least partially under the inhibitory control of the baroreceptor input.     

Improvement in diastolic intraventricular pressure gradients in patients with HOCM after ethanol septal reduction

We sought to validate measurement of intraventricular pressure gradients (IVPG) and analyze their change in patients with hypertrophic obstructive cardiomyopathy (HOCM) after ethanol septal reduction (ESR). Quantitative analysis of color M-mode Doppler (CMM) images may be used to estimate diastolic IVPG noninvasively. Noninvasive IVPG measurement was validated in 10 patients undergoing surgical myectomy. Echocardiograms were then analyzed in 19 patients at baseline and after ESR. Pulsed Doppler data through the mitral valve and pulmonary venous flow were obtained. CMM was used to obtain the flow propagation velocity (Vp) and to calculate IVPG off-line. Left atrial pressure was estimated with the use of previously validated Doppler equations. Data were compared before and after ESR. CMM-derived IVPG correlated well with invasive measurements obtained before and after surgical myectomy [r = 0.8, P < 0.01, Delta(CMM - invasive IVPG) = 0.09 +/- 0.45 mmHg]. ESR resulted in a decrease of resting LVOT systolic gradient from 62 +/- 10 to 29 +/- 5 mmHg (P < 0.001). There was a significant increase in the Vp and IVPG (from 48 +/- 5to 74 +/- 7 cm/s and from 1.5 +/- 0.2 to 2.6 +/- 0.3 mmHg, respectively, P < 0.001 for both). Estimated left atrial pressure decreased from 16.2 +/- 1.1 to 11.5 +/- 0.9 mmHg (P < 0.001). The increase in IVPG correlated with the reduction in the LVOT gradient (r = 0.6, P < 0.01). Reduction of LVOT obstruction after ESR is associated with an improvement in diastolic suction force. Noninvasive measurements of IVPG may be used as an indicator of diastolic function improvement in HOCM.     

Effects of aortic coarctation on aortic antioxidant enzymes and NADPH oxidase protein expression

Abdominal aortic coarctation above the renal arteries leads to severe hypertension above the stenotic site and provides a model for simultaneous testing of the effects of increased and decreased pressure and consequently shear stress in the same animal. The effects of increased pressure, per se, on oxidative stress and antioxidant enzyme expression is unknown. We studied the protein expressions of antioxidant enzymes and NADPH oxidase (gp91phox subunit) in the aortic segments above and below the stenosis site in sham-operated control and aortic-banded rats at four weeks postoperatively. Compared with the control group, the banded group showed significant up-regulation of NADPH oxidase, catalase (CAT), Cu/Zn superoxide dismutase (SOD) and Mn SOD protein content in the thoracic aorta. In contrast, Mn SOD, Cu/Zn SOD and NADPH oxidase protein abundance were unchanged in the abdominal aortic segment below the stricture where blood pressure is not elevated, whereas CAT protein abundance was also elevated in the abdominal aorta. No changes were noted for glutathione peroxidase (GPX) protein content either in the thoracic or abdominal aortic segments. Coarctation-induced hypertension is associated with increased aortic CAT, Cu/Zn SOD, Mn SOD and NADPH oxidase protein expression. The up-regulation of NADPH oxidase increases reactive oxygen species (ROS) generation noted in the present study and contributes to inactivation of nitric oxide (NO) as shown previously in this model. Upregulation of antioxidant enzymes may be a compensatory response in the face of elevated pressure and oxidative stress. The normality of protein abundance in the abdominal aorta wherein blood pressure is not elevated points to the role of baromechanical factors, as opposed to circulating humoral factors that were similar in both segments, as a mechanism responsible for increased antioxidant enzyme expression.     

Roentgeno-endovascular dilation of aortic coarctation]

The potentialities of roentgeno-endovascular dilation (RED) of various types of coarctation and aortic stenoses were studied in 12 patients aged 9 to 27. RED was performed by two Grüntzig's catheters with balloons not less than 7 mm in diameter. The main criterion of RED efficacy was a gradient of systolic pressure which was on the decrease by 25-40 mm Hg after using one catheter, and by 40-70 mm Hg after using both catheters. The same method was applied to dilation of stenosis of the abdominal aorta. The proposed method is low invasive and most effective in patients with aortic segmentation of segmental type, and makes it possible to avoid in many cases surgical intervention.     

Fatty streak development in the vicinity of aortic coarctations in hypercholesterolemic rabbits

The influence of altered local hemodynamics on fatty streak development in rabbits fed high cholesterol diets was investigated. An aortic coarctation was created in the abdominal aorta of nine rabbits by placing a partially constricting gold or silver band (1.7 mm x 10 mm) around the aorta between the renal arteries and aortic bifurcation. Controls were 20 rabbits; seven sham operated and 13 unoperated rabbits. The abdominal aorta 1-2 cm proximal to the coarctation showed lipid deposition involving 45 +/- 8% (mean +/- SEM) of the luminal surface which was more than occurred within or distal to the obstruction (p less than 0.05) and also more than in controls (p less than 0.05). Within the coarctation, 4 +/- 2% of the luminal surface showed lipid deposition which was less than either proximally or distally (p less than 0.01) and also less than in comparable regions in controls (p less than 0.05). The aorta 1-2 cm distal to the coarctation showed lipid deposition involving 18 +/- 4% of the surface which was similar to control rabbits. Lipid deposition in corresponding regions of the control rabbits was involved in 17 +/- 4%, 19 +/- 5% and 19 +/- 4% of the luminal surface, respectively. Fatty streak development, therefore, appeared to be inhibited within the coarctation and enhanced proximal to it. The results suggest that some early step in the process of lipid accumulation may be affected by local fluid dynamics or modification of the wall of the vessel.     

The pressure dependent dynamic elasticity of 35 thoracic and 16 abdominal human aortas in vitro described by a five component model

Segments of 35 thoracic and 16 abdominal human aortas, including nine pairs, aged 30-78 yr at autopsy, were perfused with 37 degrees C Tyrode's solution at in situ length. Diameter changes due to 20 mmHg pressure steps between 20 and 180 mmHg were measured to 1 micron accuracy at an equivalent noise level of 0.1 micron RMS, using balanced transducers. Aortic creep curves at each pressure level were described individually by a constant plus bi-exponential creep model characterized by two creep fractions (alpha 1 and alpha 2) and two time constants (tau 1 and tau 2). Creep fractions and time constants increased substantially with the pressure level, indicating a significant effect of pressure or distension on aortic viscoelasticity. At 110 mmHg the mean +/- 1 S.D. parameter values were: thoracic aorta: alpha 1 = 0.076 +/- 0.017, alpha 2 = 0.102 +/- 0.028, tau 1 = 0.73 +/- 0.29 s, tau 2 = 14.0 +/- 4.1 s; abdominal aorta: alpha 1 = 0.078 +/- 0.017, alpha 2 = 0.101 +/- 0.025, tau 1 = 0.61 +/- 0.12 s, tau 2 = 12.1 +/- 3.4 s. Nine paired comparisons at each pressure level showed that creep fractions and time constants of thoracic and abdominal segments were not significantly different (p = 0.05).     

Estimation of valvular resistance of segmented aortic valves using computational fluid dynamics

Aortic valve stenosis is associated with an elevated left ventricular pressure and transaortic pressure drop. Clinicians routinely use Doppler ultrasound to quantify aortic valve stenosis severity by estimating this pressure drop from blood velocity. However, this method approximates the peak pressure drop, and is unable to quantify the partial pressure recovery distal to the valve. As pressure drops are flow dependent, it remains difficult to assess the true significance of a stenosis for low-flow low-gradient patients. Recent advances in segmentation techniques enable patient-specific Computational Fluid Dynamics (CFD) simulations of flow through the aortic valve. In this work a simulation framework is presented and used to analyze data of 18 patients. The ventricle and valve are reconstructed from 4D Computed Tomography imaging data. Ventricular motion is extracted from the medical images and used to model ventricular contraction and corresponding blood flow through the valve. Simplifications of the framework are assessed by introducing two simplified CFD models: a truncated time-dependent and a steady-state model. Model simplifications are justified for cases where the simulated pressure drop is above 10 mmHg. Furthermore, we propose a valve resistance index to quantify stenosis severity from simulation results. This index is compared to established metrics for clinical decision making, i.e. blood velocity and valve area. It is found that velocity measurements alone do not adequately reflect stenosis severity. This work demonstrates that combining 4D imaging data and CFD has the potential to provide a physiologically relevant diagnostic metric to quantify aortic valve stenosis severity.     

Fluid Dynamics of Coarctation of the Aorta and Effect of Bicuspid Aortic Valve

Up to 80% of patients with coarctation of the aorta (COA) have a bicuspid aortic valve (BAV). Patients with COA and BAV have elevated risks of aortic complications despite successful surgical repair. The development of such complications involves the interplay between the mechanical forces applied on the artery and the biological processes occurring at the cellular level. The focus of this study is on hemodynamic modifications induced in the aorta in the presence of a COA and a BAV. For this purpose, numerical investigations and magnetic resonance imaging measurements were conducted with different configurations: (1) normal: normal aorta and normal aortic valve; (2) isolated COA: aorta with COA (75% reduction by area) and normal aortic valve; (3) complex COA: aorta with the same severity of COA (75% reduction by area) and BAV. The results show that the coexistence of COA and BAV significantly alters blood flow in the aorta with a significant increase in the maximal velocity, secondary flow, pressure loss, time-averaged wall shear stress and oscillatory shear index downstream of the COA. These findings can contribute to a better understanding of why patients with complex COA have adverse outcome even following a successful surgery.     

Echocardiographic assessment of aortic elastic properties with automated border detection in an ICU: in vivo application of the arctangent Langewouters model

We studied whether combined pressure and transesophageal ultrasound monitoring is feasible in the intensive care unit (ICU) setting for global cardiovascular hemodynamic monitoring [systemic vascular resistance (SVR) and total arterial compliance (C(PPM))] and direct estimation of local ascending and descending aortic mechanical properties, i.e., distensibility and compliance coefficients (DC and CC). Pressure-area data were fitted to the arctangent Langewouters model, with aortic cross-sectional area obtained via automated border detection. Data were measured in 19 subjects at baseline, during infusion of sodium nitroprusside (SNP), and after washout. SNP infusion lowered SVR from 1.15 +/- 0.40 to 0.80 +/- 0.32 mmHg.ml(-1).s (P < 0.05), whereas C(PPM) increased from 0.87 +/- 0.46 to 1.02 +/- 0.42 ml/mmHg (P < 0.05). DC and CC increased from 0.0018 +/- 0.0007 to 0.0025 +/- 0.0009 l/mmHg (P < 0.05) and from 0.0066 +/- 0.0028 to 0.0083 +/- 0.0026 cm2/mmHg (P < 0.05), respectively, at the descending, but not ascending, aorta. The Langewouters model fitted the descending aorta data reasonably well. Assessment of local mechanical properties of the human ascending aorta in a clinical setting by automated border detection remains technically challenging.     

Coarctation of the aorta in adults.

Thirty-six patients, 19 men and 17 women, presented at age 18 or older between 1952 and 1974 with coarctation of the aorta. Of the 14 (39%) who had associated cardiovascular disease, 12 had aortic stenosis or insufficiency or both. Three patients had infections-two, endocarditis (aortic valve) and one, endarteritis. Three of the seven patients who did not undergo an operation are alive, two at more than 50 years of age. Five patients had myocardial infarctions, two at 35 years of age. Twenty-nine (80%) had operations; in eight instances the patient was over age 40. All 18 patients undergoing repair of isolated coarctation survived, while only 7 of the 11 patients with associated cardiovascular lesions who underwent repair recovered. Aortic valvular disease and myocardial infarction are serious complicating factors in coarctation of the aorta.     

Comparison of Central Aortic and Peripheral Artery Pressure Curves

Brachial artery and central aortic pressures were compared in 50 consecutive patients subjected to retrograde left heart catheterization in order to re-emphasize the fact that the two pressures are not necessarily identical. In 43 cases the systemic systolic pressure peaks exceeded those in the central aorta while in seven these pressures were equal. The average pressure difference was 22.6 mm. Hg. The greatest differences occurred in cases of aortic regurgitation and could be extreme, the brachial artery systolic pressure exceeding that in the aorta by more than 100 mm. Hg in some instances. The least differences occurred in cases of aortic stenosis but significant differences occasionally existed, leading to erroneous estimation of valve orifice size if the systemic rather than the aortic systolic pressure was used.     

Unloading arterial baroreceptors causes neurogenic hypertension

We developed a new model to examine the role of arterial baroreceptors in the long-term control of mean arterial pressure (MAP) in dogs. Baroreceptors in the aortic arch and one carotid sinus were denervated, and catheters were implanted in the descending aorta and common carotid arteries. MAP and carotid sinus pressure (CSP) averaged 104 +/- 2 and 102 +/- 2 mmHg (means +/- 1 SE), respectively, during a 5-day control period. Baroreceptor unloading was induced by ligation of the common carotid artery proximal to the innervated sinus (n = 6 dogs). MAP and CSP averaged 127 +/- 7 and 100 +/- 3 mmHg, respectively, during the 7-day period of baroreceptor unloading. MAP was significantly elevated (P < 0.01) compared to control, but CSP was unchanged. Heart rate and plasma renin activity increased significantly in response to baroreceptor unloading. Removal of the ligature to restore normal flow through the carotid resulted in normalization of all variables. Ligation of the carotid below a denervated sinus (n = 4) caused a significant decrease in CSP but no systemic hypertension. These results indicate that chronic unloading of carotid baroreceptors can produce neurogenic hypertension and provide strong evidence that arterial baroreceptors are involved in the long-term control of blood pressure.     

Computational simulations for aortic coarctation: representative results from a sampling of patients

Treatments for coarctation of the aorta (CoA) can alleviate blood pressure (BP) gradients (Δ), but long-term morbidity still exists that can be explained by altered indices of hemodynamics and biomechanics. We introduce a technique to increase our understanding of these indices for CoA under resting and nonresting conditions, quantify their contribution to morbidity, and evaluate treatment options. Patient-specific computational fluid dynamics (CFD) models were created from imaging and BP data for one normal and four CoA patients (moderate native CoA: Δ12 mmHg, severe native CoA: Δ25 mmHg and postoperative end-to-end and end-to-side patients: Δ0 mmHg). Simulations incorporated vessel deformation, downstream vascular resistance and compliance. Indices including cyclic strain, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were quantified. Simulations replicated resting BP and blood flow data. BP during simulated exercise for the normal patient matched reported values. Greatest exercise-induced increases in systolic BP and mean and peak ΔBP occurred for the moderate native CoA patient (SBP: 115 to 154 mmHg; mean and peak ΔBP: 31 and 73 mmHg). Cyclic strain was elevated proximal to the coarctation for native CoA patients, but reduced throughout the aorta after treatment. A greater percentage of vessels was exposed to subnormal TAWSS or elevated OSI for CoA patients. Local patterns of these indices reported to correlate with atherosclerosis in normal patients were accentuated by CoA. These results apply CFD to a range of CoA patients for the first time and provide the foundation for future progress in this area.     

Early mitral deceleration and left atrial stiffness

Left ventricular (LV) filling deceleration time (DT) is determined by the sum of atrial and ventricular stiffnesses (KLA + KLV). If KLA, however, is close to zero, then DT would reflect KLV only. The purpose of this study was to quantify KLA during DT. In 15 patients, KLV was assessed, immediately after cardiopulmonary bypass, from E wave DT as derived from mitral tracings obtained by transesophageal echocardiography and computed according to a validated formula. In each patient, a left atrial (LA) volume curve was also obtained combining mitral and pulmonary vein (PV) cumulative flow plus LA volume measured at end diastole. Time-adjusted LA pressure was measured simultaneously with Doppler data in all patients. KLA was then calculated during the ascending limb of the V loop and during DT. LA volume decreased by 7.3 +/- 6.5 ml/m2 during the first of mitral DT, whereas LV volume increased 9.4 +/- 8.4 ml/m2 (both P < 0.001). There was a small amount of blood coming from the PV during the same time interval, with the cumulative flow averaging 3.2 +/- 2.4 ml/m(2) (P < 0.001). Mean LA pressure was 10.0 +/- 5.1 mmHg, and it did not change during DT [from 7.8 +/- 4.3 to 8.0 +/- 4.3 mmHg, not significant (NS)], making KLA, which averaged 0.46 +/- 0.39 mmHg/ml during the V loop, close to zero during DT [KLA(DT): from -0.002 +/- 0.08 to -0.001 +/- 0.031 mmHg/ml, NS]. KLV, as assessed noninvasively from DT, averaged 0.25 +/- 0.32 mmHg/ml. In conclusion, notwithstanding the significant decrement in LA volume, KLA does not change and can be considered not different from zero during DT. Thus KLA does not affect the estimation of KLV from Doppler parameters.     

Measurement of aortic input impedance in mice: effects of age on aortic stiffness

Mice are used with increasing frequency as models of human cardiovascular diseases, but significant gaps exist in our knowledge of vascular function in the aging mouse. We determined aortic input impedance spectra, pulse wave velocity, and augmentation index in adult (8-mo-old) and old (29-mo-old) mice to determine whether arterial stiffening occurred with age in mice as it does in humans. Pressure and blood velocity signals measured simultaneously from the same location in the ascending aorta were used to determine input impedance spectra (0-10 harmonics). The first minimum of the impedance modulus occurred at the second harmonic in adult mice but shifted to the fourth harmonic in old mice. Characteristic impedance (average of 2nd-10th harmonic) was 57% higher in old mice: 471 +/- 62 vs. 299 +/- 10 (SE) dyn.s.cm-3 (P < 0.05). Pulse pressure and augmentation index, determined from the aortic pressure signals, were also higher in old mice: 42 +/- 2.2 vs. 29 +/- 4.9 mmHg (P < 0.05) and 37 +/- 5 vs. 14 +/- 2% (P < 0.005). Aortic pulse wave velocity measured from the timing of upstrokes of the Doppler velocity signals was 45% higher in old mice: 416 +/- 22 vs. 286 +/- 14 cm/s (n = 3, P < 0.01). These results reproduce age-related findings reported in humans and confirm that mice may be used as models of age-related vascular stiffening.