Hemodynamic response to thermal stress varies with sex and age: a murine MRI study.

PURPOSE: The cardiovascular (CV) system plays a vital role in thermoregulation because of its influence on heat transfer via forced convection and conduction by changes in blood distribution, blood velocity, and proximity of vessels to surrounding tissues. To fully understand the cardiovascular system's role in thermoregulation, blood distribution (influenced by cardiac output, vessel size, blood flow, and pressure) must be quantified, ideally across sex and age. Additionally, wall shear stress is quantified because it is an important metric in cardiovascular disease localization and progression. By investigating the effect of thermal conditions on wall shear stress at a healthy baseline, researchers can begin to study the confluence of thermal condition with pathology or exercise. The purpose of this study is to determine the influence of sex and age on the CV response to temperature. In this work, the effect of core body temperature on hemodynamics of the murine arterial and venous systems has been studied non-invasively, at multiple locations across age and sex. METHODS: Male and female, adult and aged, mice (n = 20) were anesthetized and underwent MRI at 7 T. Data were acquired from four co-localized vessel pairs (the neck [carotid/jugular], torso [suprarenal and infrarenal aorta/inferior vena cava (IVC)], periphery [femoral artery/vein]) at core temperatures of 35, 36, 37, and 38 °C. Sixteen CINE, ECG-gated, phase contrast frames with one-directional velocity encoding (through plane) were acquired perpendicular to each vessel. Each frame was analyzed to quantify blood velocity and volumetric flow using a semi-automated in-house MATLAB script. Wall shear stress (WSS) was calculated using the Hagen-Poiseulle formula. A multivariable regression for WSS in the femoral artery was fitted with temperature, sex, age, body weight, and heart rate as variables. RESULTS: Blood velocity and volumetric flow were quantified in eight vessels at four core body temperatures. Flow in the infrarenal IVC linearly increased with temperature for all groups (p = .002; adjusted means of slopes: male vs. female, 0.37 and 0.28 cm/(s × °C); adult vs. aged, 0.22 and 0.43 cm/(s × °C)). Comparing average volumetric flow response to temperature, groups differed for the suprarenal aorta (adult < aged, p < .05), femoral artery (adult < aged, p < .05), and femoral vein (adult male < aged male, p < .001). The two-way interaction terms of temperature and body weight and temperature and sex had the largest effect on wall shear stress. CONCLUSIONS: Age, in particular, had a significant impact on hemodynamic response as measured by volumetric flow (e.g., aged males > adult males) and WSS at peak-systole (e.g., aged males < adult males). The hemodynamic data can provide physiologically-relevant parameters, including sex and age difference, to computational fluid dynamics models and provide baseline data for the healthy murine vasculature to use as a benchmark for investigations of a variety of physiological (thermal stress) and pathophysiological conditions of the cardiovascular system.

Imaging-based characterization of convective tissue properties.

Convective transport is an important phenomenon for nanomedicine delivery. We present an imaging-based approach to recover tissue properties that are significant in the accumulation of nanoparticles delivered via systemic methods. The classical pharmacokinetic analysis develops governing equations for the particle transport from a first principle mass balance. Fundamentally, the governing equations for compartmental mass balance represent a spatially invariant mass transport between compartments and do not capture spatially variant convection phenomena. Further, the parameters recovered from this approach do not necessarily have direct meaning with respect to the governing equations for convective transport. In our approach, a framework is presented for directly measuring permeability in the sense of Darcy flow through porous tissue. Measurements from our approach are compared to an extended Tofts model as a control. We demonstrate that a pixel-wise iterative clustering algorithm may be applied to reduce the parameter space of the measurements. We show that measurements obtained from our approach are correlated with measurements obtained from the extended Tofts model control. These correlations demonstrate that the proposed approach contains similar information to an established compartmental model and may be useful in providing an alternative theoretical framework for parameterizing mathematical models for treatment planning and diagnostic studies involving nanomedicine where convection dominated effects are important.

In Vivo MRI Assessment of Blood Flow in Arteries and Veins from Head-to-Toe Across Age and Sex in C57BL/6 Mice.

Although widely used as a preclinical model for studying cardiovascular diseases, there is a scarcity of in vivo hemodynamic measurements of the naïve murine system in multiple arterial and venous locations, from head-to-toe, and across sex and age. The purpose of this study is to quantify cardiovascular hemodynamics in mice at different locations along the vascular tree while evaluating the effects of sex and age. Male and female, adult and aged mice were anesthetized and underwent magnetic resonance imaging. Data were acquired from four co-localized vessel pairs (carotid/jugular, suprarenal and infrarenal aorta/inferior vena cava (IVC), femoral artery/vein) at normothermia (core temperature 37 ± 0.2 °C). Influences of age and sex on average velocity differ by location in arteries. Average arterial velocities, when plotted as a function of distance from the heart, decrease nearly linearly from the suprarenal aorta to the femoral artery (adult and aged males: - 0.33 ± 0.13, R2 = 0.87; - 0.43 ± 0.10, R2 = 0.95; adult and aged females: - 0.23 ± 0.07, R2 = 0.91; - 0.23 ± 0.02, R2 = 0.99). Average velocity of aged males and average volumetric flow of aged males and females tended to be larger compared to adult comparators. With cardiovascular disease as the leading cause of death and with the implications of cardiovascular hemodynamics as important biomarkers for health and disease, this work provides a foundation for sex and age comparisons in pathophysiology by collecting and analyzing hemodynamic data for the healthy murine arterial and venous system from head-to-toe, across sex and age.

Anatomical location, sex, and age influence murine arterial circumferential cyclic strain before and during dobutamine infusion.

BACKGROUND: One of the primary biomechanical factors influencing arterial health is their deformation across the cardiac cycle, or cyclic strain, which is often associated with arterial stiffness. Deleterious changes in the cardiovascular system, e.g., increased arterial stiffness, can remain undetected until the system is challenged, such as under a cardiac stressor like dobutamine. PURPOSE: To quantify cyclic strain in mice at different locations along the arterial tree prior to and during dobutamine infusion, while evaluating the effects of sex and age. STUDY TYPE: Control/cohort study. ANIMAL MODEL: Twenty C57BL/6 mice; male, female; ∼12 and 24 weeks of age; n = 5 per group. FIELD STRENGTH/SEQUENCE: 7T; CINE MRI with 12 frames, velocity compensation, and prospective cardiac gating. ASSESSMENT: Prior to and during the infusion of dobutamine, Green-Lagrange circumferential cyclic strain was calculated from perimeter measurements derived from CINE data acquired at the carotid artery, suprarenal and infrarenal abdominal aorta, and iliac artery. STATISTICAL TESTS: Analysis of variance (ANOVA) followed by post-hoc tests was used to evaluate the influence of dobutamine, anatomical location, sex, and age. RESULTS: Heart rates did not differ between groups prior to or during dobutamine infusion (P = 0.87 and P = 0.08, respectively). Dobutamine increased cyclic strain in each group. Within a group, increases in strain were similar across arteries. At the suprarenal aorta, strain was reduced in older mice at baseline (young 27.6 > mature 19.3%, P = 0.01) and during dobutamine infusion (young 53.0 > mature 36.2%, P = 0.005). In the infrarenal aorta, the response (dobutamine - baseline) was reduced in older mice (young 21.9 > mature 13.5%, P = 0.04). DATA CONCLUSION: Dobutamine infusion increases circumferential cyclic strain throughout the arterial tree of mice. This effect is quantifiable using CINE MRI. The results demonstrate that strain prior to and during dobutamine is influenced by anatomical location, sex, and age. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:69-80.

Cross-sectional area of the murine aorta linearly increases with increasing core body temperature.

PURPOSE: The cardiovascular (CV) system plays a vital role in thermoregulation. To date, the response of core vasculature to increasing core temperature has not been adequately studied in vivo. Our objective was to non-invasively quantify the arterial response in murine models due to increases in body temperature, with a focus on core vessels of the torso and investigate whether responses were dependent on sex or age. METHODS: Male and female, adult and aged mice were anaesthetised and underwent magnetic resonance imaging (MRI). Data were acquired from the circle of Willis (CoW), heart, infrarenal aorta and peripheral arteries at core temperatures of 35, 36, 37 and 38 °C (±0.2 °C). RESULTS: Vessels in the CoW did not change. Ejection fraction decreased and cardiac output (CO) increased with increasing temperature in adult female mice. Cross-sectional area of the aorta increased significantly and linearly with temperature for all groups, but at a diminished rate for aged animals (p < 0.01; male and female: adult, 0.019 and 0.024 mm2/°C; aged, 0.017 and 0.011 mm2/°C). Aged male mice had a diminished response in the periphery (% increase in femoral artery area from 35 to 38 °C, male and female: adult, 67 and 65%; aged, 0.1 and 57%). CONCLUSION: Previously unidentified increases in aortic area due to increasing core temperature are biologically important because they may affect conductive and convective heat transfer. Leveraging non-invasive methodology to quantify sex and age dependent vascular responses due to increasing core temperature could be combined with bioheat modelling in order to improve understanding of thermoregulation.

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model.

Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.

Hemodynamic Impact of Superior Vena Cava Placement in the Y-Graft Fontan Connection.

BACKGROUND: A Fontan Y-shaped graft using a commercially available aortoiliac graft has been used to connect the inferior vena cava (IVC) to the pulmonary arteries. This modification of the Fontan procedure seeks to improve hepatic flow distribution (HFD) to the lungs. However, patient-specific anatomical restrictions might limit the space available for graft placement. Altering the superior vena cava (SVC) positioning is hypothesized to provide more space for an optimal connection, avoiding caval flow collision. Computational modeling tools were used to retrospectively study the effect of SVC placement on Y-graft hemodynamics. METHODS: Patient-specific anatomies (N = 10 patients) and vessel flows were reconstructed from retrospective cardiac magnetic resonance (CMR) images after Fontan Y-graft completion. Alternative geometries were created using a virtual surgery environment, altering the SVC position and the offset in relation to the Y-graft branches. Geometric characterization and computational fluid dynamics simulations were performed. Hemodynamic factors (power loss and HFD) were computed. RESULTS: Patients with a higher IVC return showed less sensitivity to SVC positioning. Patients with low IVC flow showed varied HFD results, depending on SVC location. Balanced HFD values (50% to each lung) were obtained when the SVC lay completely between the Y-graft branches. The effect on power loss was patient specific. CONCLUSIONS: SVC positioning with respect to the Y-graft affects HFD, especially in patients with lower IVC flow. Careful positioning of the SVC at the time of a bidirectional Glenn (BDG) procedure based on patient-specific anatomy can optimize the hemodynamics of the eventual Fontan completion.