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DOE OSTI2022

Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification

Abstract Aim Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. Methods and results A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9–14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2–37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15–1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02–1.65), but not with AVC progression (β: −71 AU for each 50 mg/dL higher Lp(a); 95% CI −117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). Conclusion In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.

Kaiser, Yannick (ORCID:0000000168690042)↗

DOE OSTI2023

Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database

Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. The study population included 3,812,588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62–8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80–6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25–5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68–4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93–5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82–13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44–3.29]) compared with controls. Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. In conclusion, this study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

The progeria research foundation 10 th international scientific workshop; researching possibilities, ExTENding lives – webinar version scientific summary

Progeria is an ultra-rare (prevalence 1 in 20 million), fatal, pediatric autosomal dominant premature aging disease caused by a mutation in the LMNA gene. This mutation results in accumulation of a high level of an aberrant form of the nuclear membrane protein, Lamin A. This aberrant protein, termed progerin, accumulates in many tissues and is responsible for the diverse array of disease phenotypes. Children die predominantly from premature atherosclerotic cardiovascular disease. The Progeria Research Foundation’s 10th International Scientific Workshop took place via webinar on November 2 and 3, 2020. Participants from 30 countries joined in this new, virtual meeting format. Patient family presentations led the program, followed by updates on Progeria’s first-ever application for FDA drug approval as well as initial results from the only current Progeria clinical trial. This was followed by presentations of unpublished preclinical data on drugs in development targeting the disease-causing DNA mutation, the aberrant mRNA, progerin protein, and its downstream effector proteins. Tying bench to bedside, clinicians presented new discoveries on the natural history of disease to inform future clinical trial development and new Progeria aortic valve replacement procedures. The program engaged the Progeria research community as a single unit with a common goal – to treat and cure children with Progeria worldwide.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Design and execution of a verification, validation, and uncertainty quantification plan for a numerical model of left ventricular flow after LVAD implantation

Left ventricular assist devices (LVADs) are implantable pumps that act as a life support therapy for patients with severe heart failure. Despite improving the survival rate, LVAD therapy can carry major complications. Particularly, the flow distortion introduced by the LVAD in the left ventricle (LV) may induce thrombus formation. While previous works have used numerical models to study the impact of multiple variables in the intra-LV stagnation regions, a comprehensive validation analysis has never been executed. The main goal of this work is to present a model of the LV-LVAD system and to design and follow a verification, validation and uncertainty quantification (VVUQ) plan based on the ASME V&V40 and V&V20 standards to ensure credible predictions. The experiment used to validate the simulation is the SDSU cardiac simulator, a bench mock-up of the cardiovascular system that allows mimicking multiple operation conditions for the heart-LVAD system. The numerical model is based on Alya, the BSC’s in-house platform for numerical modelling. Alya solves the Navier-Stokes equation with an Arbitrary Lagrangian-Eulerian (ALE) formulation in a deformable ventricle and includes pressure-driven valves, a 0D Windkessel model for the arterial output and a LVAD boundary condition modeled through a dynamic pressure-flow performance curve. The designed VVUQ plan involves: (a) a risk analysis and the associated credibility goals; (b) a verification stage to ensure correctness in the numerical solution procedure; (c) a sensitivity analysis to quantify the impact of the inputs on the four quantities of interest (QoIs) (average aortic root flow $Q^{avg}_{Ao}$, maximum aortic root flow $Q^{max}_{Ao}$, average LVAD flow $Q^{avg}_{VAD}$, and maximum LVAD flow $Q^{max}_{VAD}$; (d) an uncertainty quantification using six validation experiments that include extreme operating conditions. Numerical code verification tests ensured correctness of the solution procedure and numerical calculation verification showed a grid convergence index (GCI)95% <3.3%. The total Sobol indices obtained during the sensitivity analysis demonstrated that the ejection fraction, the heart rate, and the pump performance curve coefficients are the most impactful inputs for the analysed QoIs. The Minkowski norm is used as validation metric for the uncertainty quantification. It shows that the midpoint cases have more accurate results when compared to the extreme cases. The total computational cost of the simulations was above 100 [core-years] executed in around three weeks time span in Marenostrum IV supercomputer. This work details a novel numerical model for the LV-LVAD system, that is supported by the design and execution of a VVUQ plan created following recognised international standards. We present a methodology demonstrating that stringent VVUQ according to ASME standards is feasible but computationally expensive.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Multiscale embedded printing of engineered human tissue and organ equivalents

Creating tissue and organ equivalents with intricate architectures and multiscale functional feature sizes is the first step toward the reconstruction of transplantable human tissues and organs. Existing embedded ink writing approaches are limited by achievable feature sizes ranging from hundreds of microns to tens of millimeters, which hinders their ability to accurately duplicate structures found in various human tissues and organs. In this study, a multiscale embedded printing (MSEP) strategy is developed, in which a stimuli-responsive yield-stress fluid is applied to facilitate the printing process. A dynamic layer height control method is developed to print the cornea with a smooth surface on the order of microns, which can effectively overcome the layered morphology in conventional extrusion-based three-dimensional bioprinting methods. Since the support bath is sensitive to temperature change, it can be easily removed after printing by tuning the ambient temperature, which facilitates the fabrication of human eyeballs with optic nerves and aortic heart valves with overhanging leaflets on the order of a few millimeters. The thermosensitivity of the support bath also enables the reconstruction of the full-scale human heart on the order of tens of centimeters by on-demand adding support bath materials during printing. Here, the proposed MSEP demonstrates broader printable functional feature sizes ranging from microns to centimeters, providing a viable and reliable technical solution for tissue and organ printing in the future.

3D bioprinting↗