Aortic Biomechanics Research Articles

Co-localization of microstructural damage and excessive mechanical strain at aortic branches in angiotensin-II-infused mice.

Animal models of aortic aneurysm and dissection can enhance our limited understanding of the etiology of these lethal conditions particularly because early-stage longitudinal data are scant in humans. Yet, the pathogenesis of often-studied mouse models and the potential contribution of aortic biomechanics therein remain elusive. In this work, we combined micro-CT and synchrotron-based imaging with computational biomechanics to estimate in vivo aortic strains in the abdominal aorta of angiotensin-II-infused ApoE-deficient mice, which were compared with mouse-specific aortic microstructural damage inferred from histopathology. Targeted histology showed that the 3D distribution of micro-CT contrast agent that had been injected in vivo co-localized with precursor vascular damage in the aortic wall at 3days of hypertension, with damage predominantly near the ostia of the celiac and superior mesenteric arteries. Computations similarly revealed higher mechanical strain in branching relative to non-branching regions, thus resulting in a positive correlation between high strain and vascular damage in branching segments that included the celiac, superior mesenteric, and right renal arteries. These results suggest a mechanically driven initiation of damage at these locations, which was supported by 3D synchrotron imaging of load-induced ex vivo delaminations of angiotensin-II-infused suprarenal abdominal aortas. That is, the major intramural delamination plane in the ex vivo tested aortas was also near side branches and specifically around the celiac artery. Our findings thus support the hypothesis of an early mechanically mediated formation of microstructural defects at aortic branching sites that subsequently propagate into a macroscopic medial tear, giving rise to aortic dissection in angiotensin-II-infused mice.

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

In computational aortic biomechanics, aortic and arterial tissue are typically modelled as a homogeneous layer, making abstraction not only of the layered structure of intima, media and adventitia but also of the microstructure that exists within these layers. Here, we present a novel method to visualize the microstructure of the tunica media along the entire circumference of the vessel. To that end, we developed a pressure-inflation device that is compatible with synchrotron-based phase-contrast imaging. Using freshly excised left common carotid arteries from n = 12 mice, we visualized how the lamellae and interlamellar layers inflate as the luminal pressure is increased from 0 to 120 mm Hg in quasi-static steps. A graph-based segmentation algorithm subsequently allowed us to automatically segment each of the three lamellae, resulting in a three-dimensional geometry that represents lamellae, interlamellar layers and adventitia at nine different pressure levels. Our results demonstrate that the three elastic lamellae unfold and stretch simultaneously as luminal pressure is increased. In the long term, we believe that the results presented in this work can be a first step towards a better understanding of the mechanics of the arterial microstructure.

Vascular smooth muscle cell contraction and relaxation in the isolated aorta: a critical regulator of large artery compliance.

Over the past few decades, isometric contraction studies of isolated thoracic aorta segments have significantly contributed to our overall understanding of the active, contractile properties of aortic vascular smooth muscle cells (VSMCs) and their cross‐talk with endothelial cells. However, the physiological role of VSMC contraction or relaxation in the healthy aorta and its contribution to the pulse‐smoothening capacity of the aorta is currently unclear. Therefore, we investigated the acute effects of VSMC contraction and relaxation on the isobaric biomechanical properties of healthy mouse aorta. An in‐house developed set‐up was used to measure isobaric stiffness parameters of periodically stretched (10 Hz) aortic segments at an extended pressure range, while pharmacologically modulating VSMC tone and endothelial cell function. We found that the effects of α1‐adrenergic stimulation with phenylephrine on the pressure‐stiffness relationship varied in sensitivity, magnitude and direction, with the basal, unstimulated NO production by the endothelium playing a pivotal role. We also investigated how arterial disease affected this system by using the angiotensin‐II‐treated mouse. Our results show that isobaric stiffness was increased and that the aortic segments demonstrated a reduced capacity for modulating the pressure‐stiffness relationship. This suggests that not only increased isobaric stiffness at normal pressure, but also a reduced capacity of the VSMCs to limit the pressure‐associated increase in aortic stiffness, may contribute to the pathogenesis of this mouse model. Overall, this study provides more insight in how aortic VSMC tone affects the pressure‐dependency of aortic biomechanics at different physiological and pathological conditions.

Pregnancy-Induced Physiologic Adaptation of the Abdominal Aorta Is Associated with Changes in Gene Expression and Genomic Methylation

Background/Aims: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified as a master epigenetic regulator of vascular smooth muscle cell plasticity. We hypothesized that pregnancy will induce significant adaptive changes in aortic biomechanics that correlate with the Tet family gene expression. Methods: Abdominal aortas from pregnant and nonpregnant mice were dissected and cannulated. Intraluminal pressure was adjusted using a pressure-servo system while using a video dimension analyzer to measure the lumen diameter. Quantitative polymerase chain reaction and immunoblot was used to analyze the expression of Tet genes. Global genomic methylation was assessed with the luminometric methylation assay. Results: Compared to the nonpregnant (NP, 706 ± 8 µm) control group, the aortic luminal diameter was significantly increased in both E18.5 (836 ± 14 µm) and PP30 (889 ± 16 µm) mice. Distensibility was reduced in E18.5 (90 ± 4%) mice and returned to NP values (108 ± 2%) in PP30 (108 ± 3%) mice. Tet2 transcription decreased at the beginning of pregnancy and subsequently increased in late gestation, inversely corresponding to changes in global methylation. Conclusion: Physiologic changes in the aorta were accompanied by changes in gene expression and genomic methylation, suggesting an epigenetic component to maternal vascular remodeling during pregnancy.

Abstract 313: Loss of Contractile Smooth Muscle Cell Phenotype in a Mouse Model of Marfan Syndrome

Objectives: Thoracic aortic aneurysm (TAA) is a chronic vascular disease and the 15th leading cause of death in the US. TAA can result from a genetic disorder such as Marfan syndrome (MFS). MFS patients typically have fibrillin-1 deficiency, causing elastic fiber defects in the aortic media that initiate a series of cellular events. We sought to determine the association of smooth muscle cell (SMC) conversion from contractile to synthetic phenotype with changes in extracellular matrix (ECM), medial cell density, and arterial biomechanics. Methods: A mouse model of MFS (Fbn1 C1039G/+, Het) was used to study progression of TAA and cellular events over a 3-12 month time course. Small animal ultrasound was used to image the ascending aorta and to measure diameters at several positions. Immunohistochemistry (IHC) was performed on proximal aorta sections with smooth muscle-myosin heavy chain (SM-MHC) and SM alpha actin as markers for contractile SMCs. Second harmonic generation (SHG) microscopy was used to quantitate aortic medial collagen. Results: Ultrasound data show that aortic diameter significantly increases with time in Het mice. There is a statistically significant difference between genotypes independent of time. IHC images demonstrate that while SM-MHC expression in wild type (WT) mice remains nearly constant, in Het mice at 3 months the expression is comparable to that of WT mice but decreases at 6 months and starts to recover to the WT level by 12 months. SHG images show a time dependent increase in medial collagen expression in Het mice vs. WT. These results suggest loss of contractile SMCs in the media and remodeling of ECM. Conclusion: Our results to date demonstrate loss of contractile SMCs and increased medial collagen deposition in the proximal aorta during TAA progression. Loss of contractile cells together with changes in ECM are expected to alter aortic biomechanics. To quantify these alterations, we are currently studying active and passive biomechanics of ascending aortas of WT and Het mice.

Transesophageal echocardiographic strain imaging predicts aortic biomechanics: Beyond diameter

BackgroundClinical guidelines recommend resection of ascending aortic aneurysms at diameters 5.5 cm or greater to prevent rupture or dissection. However, approximately 40% of all ascending aortic dissections occur below this threshold. We propose new transesophageal echocardiography strain-imaging moduli coupled with blood pressure measurements to predict aortic dysfunction below the surgical threshold. MethodsA total of 21 patients undergoing aortic resection were recruited to participate in this study. Transesophageal echocardiography imaging of the aortic short-axis and invasive radial blood pressure traces were taken for 3 cardiac cycles. By using EchoPAC (GE Healthcare, Madison, Wis) and postprocessing in MATLAB (MathWorks, Natick, Mass), circumferential stretch profiles were generated and combined with the blood pressure traces. From these data, 2 in vivo stiffness moduli were calculated: the Cardiac Cycle Pressure Modulus and Cardiac Cycle Stress Modulus. From the resected aortic ring, testing squares were isolated for ex vivo mechanical analysis and histopathology. Each square underwent equibiaxial tensile testing to generate stress-stretch profiles for each patient. Two ex vivo indices were calculated from these profiles (energy loss and incremental stiffness) for comparison with the Cardiac Cycle Pressure Modulus and Cardiac Cycle Stress Modulus. ResultsThe echo-derived stiffness moduli demonstrate positive significant covariance with ex vivo tensile biomechanical indices: energy loss (vs Cardiac Cycle Pressure Modulus: R2 = 0.5873, P < .0001; vs Cardiac Cycle Stress Modulus: R2 = 0.6401, P < .0001) and apparent stiffness (vs Cardiac Cycle Pressure Modulus: R2 = 0.2079, P = .0378; vs Cardiac Cycle Stress Modulus: R2 = 0.3575, P = .0042). Likewise, these transesophageal echocardiography–derived moduli are highly predictive of the histopathologic composition of collagen and elastin (collagen/elastin ratio vs Cardiac Cycle Pressure Modulus: R2 = 0.6165, P < .0001; vs Cardiac Cycle Stress Modulus: R2 = 0.6037, P < .0001). ConclusionsTransesophageal echocardiography–derived stiffness moduli correlate strongly with aortic wall biomechanics and histopathology, which demonstrates the added benefit of using simple echocardiography-derived biomechanics to stratify patient populations.

Should We Ignore What We Cannot Measure? How Non-Uniform Stretch, Non-Uniform Wall Thickness and Minor Side Branches Affect Computational Aortic Biomechanics in Mice.

In order to advance the state-of-the-art in computational aortic biomechanics, we investigated the influence of (i) a non-uniform wall thickness, (ii) minor aortic side branches and (iii) a non-uniform axial stretch distribution on the location of predicted hotspots of principal strain in a mouse model for dissecting aneurysms. After 3 days of angiotensin II infusion, a murine abdominal aorta was scanned in vivo with contrast-enhanced micro-CT. The animal was subsequently sacrificed and its aorta was scanned ex vivo with phase-contrast X-ray tomographic microscopy (PCXTM). An automatic morphing framework was developed to map the non-pressurized, non-stretched PCXTM geometry onto the pressurized, stretched micro-CT geometry. The output of the morphing model was a structural FEM simulation where the output strain distribution represents an estimation of the wall deformation, not only due to the pressurization, but also due to the local axial stretch field. The morphing model also included minor branches and a mouse-specific wall thickness. A sensitivity study was then performed to assess the influence of each of these novel features on the outcome of the simulations. The results were supported by comparing the computed hotspots of principal strain to hotspots of early vascular damage as detected on PCXTM. Non-uniform axial stretch, non-uniform wall thickness and minor subcostal arteries significantly alter the locations of calculated hotspots of maximal principal strain. Even if experimental data on these features are often not available in clinical practice, one should be aware of the important implications that simplifications in the model might have on the final simulated result.

A novel approach to the quantification of aortic root in vivo structural mechanics.

Understanding aortic root in vivo biomechanics can help in elucidating key mechanisms involved in aortic root pathologies and in the outcome of their surgical treatment. Numerical models can provide useful quantitative information. For this to be reliable, detailed aortic root anatomy should be captured. Also, since the aortic root is never unloaded throughout the cardiac cycle, the modeled geometry should be consistent with the in vivo loads acting on it. Achieving such consistency is still a challenge, which was tackled only by few numerical studies. Here we propose and describe in detail a new approach to the finite element modeling of aortic root in vivo structural mechanics. Our approach exploits the anatomical information yielded by magnetic resonance imaging by reconstructing the 3-dimensional end-diastolic geometry of the aortic root and makes the reconstructed geometry consistent with end-diastolic loading conditions through the estimation of the corresponding prestresses field. We implemented our approach through a semiautomated modeling pipeline, and we applied it to quantify aortic root biomechanics in 4 healthy participants. Computed results highlighted that including prestresses into the model allowed for pressurizing the aortic root to the end-diastolic pressure while matching the image-based ground truth data. Aortic root dynamics, tissues strains, and stresses computed at relevant time points through the cardiac cycle were consistent with a broad set of data from previous computational and in vivo studies, strongly suggesting the potential of the method. Also, results highlighted the major role played by the anatomy in driving aortic root biomechanics.

Obtaining the biomechanical behavior of ascending aortic aneurysm via the use of novel speckle tracking echocardiography

IntroductionEx vivo measurement of ascending aortic biomechanical properties may help understand the risk for rupture or dissection of dilated ascending aortas. A validated in vivo method that can predict aortic biomechanics does not exist. Speckle tracking transesophageal echocardiography (TEE) has been used to measure ventricular stiffness; we sought to determine whether speckle TEE could be adapted to estimate aortic stiffness in vivo and compare these findings with those obtained by ex vivo tissue measurements. MethodsA total of 17 patients undergoing ascending aortic resection were recruited to with a mean aortic diameter was 56.16 ± 15 mm. Intraoperative speckle TEE tracking analysis was used to calculate aortic stiffness index using the following equation: β2=ln(SBP/DBP)/AoS, where β2 is the stiffness index; SBP is systolic blood pressure; DBP is diastolic blood pressure; and AoS is the circumferential strain. Ex vivo stiffness was obtained by mechanical tissue testing according to previously described methods. The aortic ring at the pulmonary trunk was divided into 4 equal quadrants. ResultsThe in vivo stiffness index for the inner curvature, anterior wall, outer curvature, and posterior wall were 0.0544 ± 0.0490, 0.0295 ± 0.0199, 0.0411 ± 0.0328, and 0.0502 ± 0.0320, respectively. The mean ex vivo 25% apparent stiffness for inner curvature, anterior wall, outer curvature, and posterior wall were 0.0616 ± 0.0758 MPa, 0.0352 ± 0.00992 MPa, 0.0405 ± 0.0199 MPa, and 0.0327 ± 0.0106 MPa, respectively. The patient-matched ex vivo 25% apparent stiffness and in vivo stiffness index were not significantly different (P = .8617, 2-way analysis of variance with repeated measures). ConclusionsThe use of speckle TEE appears to be a promising technique to estimate ex vivo mechanical properties of the ascending aortic tissue.

Abstract 19655: Elevated Oxidative Stress Induces Smooth Muscle Cell Death via Superoxide Anion in Bicuspid Aortic Valve-associated Aortopathy

Introduction: Bicuspid aortic valve (BAV) is associated with an aortopathy that manifests as a dilatation of the proximal ascending aorta. The mechanisms of aneurysm formation in BAV patients are not completely understood. Our group established that medial smooth muscle cells (SMC) from aneurysmal BAV patients exhibit a weakened oxidative stress defense. Hypothesis: The weakened oxidative stress defense of medial SMCs in BAV patients leads to elevated oxidative stress in the proximal ascending aorta and decreases SMC viability. Methods: Aortic specimens were harvested from patients undergoing aortic valve and/or ascending aortic replacement due to aneurysm, or heart transplant, with IRB approval and informed patient consent. Levels of the superoxide anion-specific oxidation product 2-OH-E + was detected via HPLC in hydroethidine-exposed fresh human aortic specimens. Lipid peroxidation was quantified by ELISA-based detection of 8-iso-prostaglandin F2α. Superoxide anion (O 2 •- ) production and cell viability in primary SMC were detected using the cytochrome c reduction assay, and the MTT assay respectively. Results: Levels of O 2 •- and lipid peroxidation were elevated in BAV specimens when compared with tricuspid aortic valve (TAV) specimens (8.7 ± 0.90 vs 6.1 ± 0.90 pmol/mg, and 610±32 vs 458±45 pg/mg, Fig A and B respectively). Elevated O 2 •- production was detected in primary SMC in vitro when compared with SMC from TAV patients (13.2 ± 2.9 vs 6.7 ± 1.7 pmol/min/mg, Fig C). Addition of peroxide to primary SMC resulted in intracellular O 2 •- -mediated cell death (Fig D). Conclusions: Our results indicate that accumulation of O 2 •- in SMC is associated with increased oxidative stress and with increased cell death in the setting of BAV. Ongoing studies are focused on defining mechanisms of O 2 •- generation and the impact on aortic wall biomechanics. Importantly, this could help to develop novel interventions for BAV patients who are at risk for aortic catastrophe.

Aortic biomechanics in hypertrophic cardiomyopathy

Background: Ventricular-vascular coupling is an important phenomenon in many cardiovascular diseases. The association between aortic mechanical dysfunction and left ventricular (LV) dysfunction is well characterized in many disease entities, but no data are available on how these changes are related in hypertrophic cardiomyopathy (HCM). Aim of the work: This study examined whether HCM alone is associated with an impaired aortic mechanical function in patients without cardiovascular risk factors and the relation of these changes, if any, to LV deformation and cardiac phenotype. Methods: 141 patients with HCM were recruited and compared to 66 age- and sex-matched healthy subjects as control group. Pulse pressure, aortic strain, stiffness and distensibility were calculated from the aortic diameters measured by M-mode echocardiography and blood pressure obtained by sphygmomanometer. Aortic wall systolic and diastolic velocities were measured using pulsed wave Doppler tissue imaging (DTI). Cardiac assessment included geometric parameters and myocardial deformation (strain and strain rate) and mechanical dyssynchrony. Results: The pulsatile change in the aortic diameter, distensibility and aortic wall systolic velocity (AWS') were significantly decreased and aortic stiffness index was increased in HCM compared to control (P < .001) In HCM AWS' was inversely correlated to age(r = − .32, P < .0001), MWT (r = − .22, P < .008), LVMI (r = − .20, P < .02), E/Ea (r = − .16, P < .03) LVOT gradient (r = − 19, P < .02) and severity of mitral regurg (r = − .18, P < .03) but not to the concealed LV deformation abnormalities or mechanical dyssynchrony. On multivariate analysis, the key determinant of aortic stiffness was LV mass index and LVOT obstruction while the role LV dysfunction in aortic stiffness is not evident in this population. Conclusion: HCM is associated with abnormal aortic mechanical properties. The severity of cardiac phenotype, not LV deformation, is interrelated to aortic stiffness in patients with HCM. The increased aortic stiffness seems to be promising module that can be added as clinical risk parameter in HCM.

Response to letter by Mkrtchyan regarding article: “Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?”

Response to letter by Mkrtchyan regarding article: “Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?”

Correspondence letter by Mkrtchyan and Fratz regarding article “Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?”

We read with interest the article “Aortic biomechanics by magneticresonance:Earlymarkersofaorticdi seaseinMarfansyndromeregardlessof aortic dilatation? ” published recently [1].First of all we want to congratulate the authors for the article.However, because Cardiovascular Magnetic Resonance (CMR) isincreasingly used to analyze the local and regional mechanical propertiesoftheaorticwall [2–14],it'sveryimportanttoclarifysomeaspects,beforethey will become clinical routine.Using CMR, Teixido-Tura et al. compared aortic distensibility(AD) of patients with Marfan syndrome with dilated and non-dilated aortic root with that of controls.Using univariate analysis Teixido-Tura et al. demonstratedlower aortic distensibility values in Marfan patients with dilatedor non-dilated aortic root compared with those of controls.Distensibility as defined by Teixido-Tura et al. is a function of thechange of the vessel area during the cardiac phases. However, bothMarfanpatientgroupshadsignificantlylargerareasoftheaortathanthecontrol group. Therefore, if the same stroke volume passes through theaorta, distensibility must be smaller in individuals with larger vesselareas. Inother words, smallerdistensibility doesn't automatically meanimpaired elasticity. It can simply be different due to initially differentvessel diameter for a given stoke volume.Therefore, distensibility can only be translated into stiffness ifthe vessel area of the three groups is equal.Hence, in our opinion, it is misleading to use elasticity, stiffnessof the vessel and distensibility as synonyms.References

Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?

BackgroundPrevious studies demonstrated the usefulness of MRI in the evaluation of aortic biomechanics in Marfan patients with aortic dilatation. However, these parameters have not been well studied in earlier stages of aortic disease. The present work aimed to study aortic biomechanics: aortic distensibility (AD) and pulse wave velocity (PWV), by MRI in Marfan patients without advanced aortic disease. MethodsEighty consecutive Marfan patients were compared with 36 age- and sex-matched controls. MRI images at the level of ascending, descending and abdominal aorta were used to determine AD and PWV. ResultsMarfan patients (27 men; age: 32.0±10.5years; mean aortic root diameter: 37.2±4.6mm) had lower AD at all levels (ascending 2.6±2.1 vs. 6.2±3.7mmHg−1·10−3, p<0.001; descending 3.1±2.0 vs. 8.3±4.2, p<0.001; and abdominal 4.5±2.2 vs. 14.0±5.2, p<0.001), higher aortic arch PWV (8.1±6.5 vs. 4.3±1.8m/s, p<0.01) and ascending-to-abdominal PWV (6.1±3.0 vs. 4.7±1.5m/s, p<0.01) compared with controls. Thirty-five Marfan patients had a non-dilated aortic root (mean aortic root diameter: 34.5±3.8mm). In multivariable analyses, after adjustment for age, pulse pressure and aortic dimensions, AD remained lower and PWV higher in Marfan patients; even Marfan patients with non-dilated aortic root showed impaired aortic biomechanics compared with controls. Z-score for ascending AD<−3.5 distinguished Marfan patients from controls with 82.5% sensitivity and 86.1% specificity. ConclusionsAortic biomechanics by MRI were abnormal in the entire aorta in Marfan patients. Moreover, Marfan patients without dilated aortic root showed clear impairment of aortic biomechanics, which suggests that they may be used as early markers of aortic involvement in these patients.

SMAD3 Deficiency Promotes Inflammatory Aortic Aneurysms in Angiotensin II–Infused Mice Via Activation of iNOS

BackgroundNinety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms‐osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3‐knockout mice.Methods and ResultsWe have shown that angiotensin II–induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in mice. Lipopolysaccharide‐triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II–infused SMAD3‐knockout mice. In contrast, phenylephrine‐triggered hypertension alone was insufficient to induce aortic aneurysms in mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed the mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re‐ChIP assays revealed that the underlying mechanism involved aberrant upregulation of inducible nitric oxide synthase (iNOS)–derived nitric oxide production and activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate‐liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS‐mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology.ConclusionsMacrophage depletion and iNOS antagonism represent 2 promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life‐threatening manifestations of AOS.

A New Method to Quantify Aortic Biomechanics In Vivo Using Four-Dimensional Magnetic Resonance Imaging (4D MRI): Implications for Ascending Aortic Endografts

A New Method to Quantify Aortic Biomechanics In Vivo Using Four-Dimensional Magnetic Resonance Imaging (4D MRI): Implications for Ascending Aortic Endografts

Going beyond ejection fraction - CMR assessment of ventricular-vascular coupling and LV remodeling predicts diastolic dysfunction in advanced ischemic cardiomyopathy

Background Increased ventricular and arterial stiffness is associated with diastolic dysfunction (DDFx) in patients with heart failure and preserved systolic function. Limited information is available regarding the impact of aortic biomechanics and the ventricular-vascular coupling (VVC) on DDFx in those patients with advanced ischemic cardiomyopathy (ICM). In addition, it is not known if cardiac magnetic resonance (CMR) measurements of LV remodeling (sphericity and scar burden) can also contribute to prediction of DDFx in these patients. We sought to examine the relationship between aortic biomechanical properties (ascending and descending distensibility, arch pulse wave velocity), ventricular-ventricular coupling (defined as the ratio between LV end-systolic elastance and effective arterial elastance), LV remodeling assessed by CMR and diastolic function assessed by echocardiography in patients with advanced ICM. Methods Patients were selected if they had undergone TTE and CMR studies within 7 days (median=1 day). 354 patients with LVEF ≤ 40% and ≥ 70% stenosis in ≥ 1c oronary artery but without prior mitral valve surgery, fused E/A waves, atrial fibrillation or > moderate mitral regurgitation were screened. Of those, 84 patients were excluded due to poor CMR image quality from artifacts and/or suboptimal temporal resolution. A total 270 charts were reviewed for demographic and laboratorial data. Diastolic function assessment was performed as per guidelines. Aortic biomechanics were measured using previously validated software (ARTFUN, INSERM U678, Paris, France) using semi-automated tracing of aortic contours with phase-contrast images and through-plane velocity encoding of the ascending and descending aorta. CMR evaluation also included long and short axis assessment of LV sphericity and function respectively on balanced steady state free precession images along with assessment of myocardial scar (on phase-sensitive inversion recovery DHE-CMR sequence ~ 10-20 minutes). Multivariate linear regression analysis was done to identify the independent predictors of DDFx. Results Males represented 76% of the cohort with a mean age of 62 ± 10 years. Mean LVEF was 23 ± 5% and DDFx was classified as either: stage 1 (44%), stage 2 (25%) or stage 3 (31%). The independent predictors of impaired diastolic function (stage > 1) are listed on Table 1. Conclusions In patients with advanced ICM, CMR assessment of VVC, LV sphericity and scar burden are independent predictors of DDFx. Aortic biomechanical properties are not independently associated with diastolic dysfunction. Funding None.

Right ventricular systolic dysfunction in patients with severe ischemic cardiomyopathy - CMR insights into an interventricular relationship

Background Right ventricular systolic dysfunction is associated with worsened outcomes and poor survival in patients with heart failure. However, it is unclear what mechanisms, other than the presence of RV infarction, contribute to the development of RV dysfunction in patients with severe ischemic cardiomyopathy. We sought to determine the impact of baseline demographic variables, CAD severity, LV diastolic function assessed by echocardiography, ventriculovascular coupling, LV remodeling, aortic biomechanical properties, and RV infarction, assessed by CMR, on RV ejection fraction. Methods Patients were selected if they had undergone TTE and CMR studies within 7 days (median=1 day). 354 patients with LVEF ≤ 40% and ≥ 70% stenosis in ≥1 coronary artery but without prior mitral valve surgery, fused E/A waves, atrial fibrillation or > moderate mitral regurgitation were included. Of those, 30 patients were excluded due to suboptimal CMR image quality for adequate RV volume tracings. A total 324 charts were reviewed for demographic and laboratorial data. Diastolic function assessment was performed as per guidelines. Aortic biomechanics were measured using previously validated software (ARTFUN, INSERM U678, Paris, France) using semi-automated tracing of aortic contours with phasecontrast images and through-plane velocity encoding of the ascending and descending aorta. CMR evaluation also included long and short axis assessment of LV/RV function respectively on balanced steady state free precession images along with assessment of LV/RV myocardial scar (on phase-sensitive inversion recovery DHE-CMR sequence ~ 10-20 minutes). Multivariate linear regression analysis performed to identify the independent predictors of RVEF. Results

Aortic Stiffness in Heritable Aortopathies: Relationship to Aneurysm Growth Rate

This study compared aortic biomechanics in different heritable aortopathy syndromes and examined the clinical utility of aortic stiffness measurements. In 218 patients (55 Marfan, 47 bicuspid aortic valve (BAV), 47 isolated familial thoracic aneurysm (FTAD) and 69 matched controls) aortic biomechanics were measured by echocardiography with simultaneous blood pressure measurements. Patients were stratified by age as ≤40 years or >40 years. Aortic stiffness increased with age and aortic biomechanics were abnormal in all aortopathies, particularly in BAV and FTAD. Increased stiffness and pulse wave velocity were seen in BAV and FTAD in both age cohorts (p<0.001) and both were stiffer than Marfan patients (p<0.01). Marfan patients aged ≤40 years had stiffer aortas than controls, but those >40 years were similar to controls. Multivariate regression identified age as the dominant correlate with increased stiffness, and also aortic diameter and mean blood pressure (R(2)=0.64; p<0.001). Aortopathy patients with stiffness index>16 had lower rate of increase in aortic diameter (0.25±0.30 mm/year) than those with normal stiffness (0.68±0.39 mm/year, p<0.001). Whilst positive predictive value of increased stiffness for detection of aortopathy was high (93% in age≤40 years, 87%, in age>40 years), negative predictive accuracy was low (55% and 34% respectively). Abnormal biomechanics are common to all aortopathies, with greater abnormality in BAV and FTAD than in Marfan. Increased aortic stiffness is associated with slower rate of aneurysm progression.

Catalase overexpression in aortic smooth muscle prevents pathological mechanical changes underlying abdominal aortic aneurysm formation

The causality of the associations between cellular and mechanical mechanisms of abdominal aortic aneurysm (AAA) formation has not been completely defined. Because reactive oxygen species are established mediators of AAA growth and remodeling, our objective was to investigate oxidative stress-induced alterations in aortic biomechanics and microstructure during subclinical AAA development. We investigated the mechanisms of AAA in an angiotensin II (ANG II) infusion model of AAA in apolipoprotein E-deficient (apoE(-/-)) mice that overexpress catalase in vascular smooth muscle cells (apoE(-/-)xTg(SMC-Cat)). At baseline, aortas from apoE(-/-)xTg(SMC-Cat) exhibited increased stiffness and the microstructure was characterized by 50% more collagen content and less elastin fragmentation. ANG II treatment for 7 days in apoE(-/-) mice altered the transmural distribution of suprarenal aortic circumferential strain (quantified by opening angle, which increased from 130 ± 1° at baseline to 198 ± 8° after 7 days of ANG II treatment) without obvious changes in the aortic microstructure. No differences in aortic mechanical behavior or suprarenal opening angle were observed in apoE(-/-)xTg(SMC-Cat) after 7 days of ANG II treatment. These data suggest that at the earliest stages of AAA development H(2)O(2) is functionally important and is involved in the control of local variations in remodeling across the vessel wall. They further suggest that reduced elastin integrity at baseline may predispose the abdominal aorta to aneurysmal mechanical remodeling.