Mouse models of cardiac disease have become essential tools in the study of pathological mechanisms, but the small size of rodents makes it challenging to quantify heart function with noninvasive imaging. Building off recent developments in high-frequency four-dimensional ultrasound (4DUS) imaging, we have applied this technology to study cardiac dysfunction progression in a murine model of metabolic cardiomyopathy. Cardiac knockout of carnitine palmitoyltransferase 2 (Cpt2M-/-) in mice hinders cardiomyocyte bioenergetic metabolism of long-chain fatty acids, and leads to progressive cardiac hypertrophy and heart failure. The proposed analysis provides a standardized approach to measure localized wall kinematics and simultaneously extract metrics of global cardiac function, LV morphometry, regional circumferential strain, and regional longitudinal strain from an interpolated 4D mesh of the endo- and epi-cardial boundaries. Comparison of metric changes due to aging suggest that circumferential strain at the base and longitudinal strain along the posterior wall are most sensitive to disease progression. We further introduce a novel Hybrid Strain Index (HSI) that incorporates information from these two regions and may have greater utility to characterize disease progression relative to other extracted metrics. Future work will look to apply these methods to additional disease models and further demonstrate the utility of metrics derived from 4DUS imaging and strain mapping.
Aim Retrospective studies suggest that mild traumatic brain injury (mTBI) in pediatric patients may lead to an increased risk of cardiac events. However, the exact functional and temporal dynamics and the associations between heart and brain pathophysiological trajectories are not understood. Methods A single impact to the left somatosensory cortical area of the intact skull was performed on juvenile mice (17 days postnatal). Cerebral 3D photoacoustic imaging was used to measure the oxygen saturation (sO2) in the impacted area 4 h after mTBI followed by 2D and 4D echocardiography at days 7, 30, 90, and 190 post‐impact. At 8 months, we performed a dobutamine stress test to evaluate cardiac function. Lastly, behavioral analyses were conducted 1 year after initial injury. Results We report a rapid and transient decrease in cerebrovascular sO2 and increased hemoglobin in the impacted left brain cortex. Cardiac analyses showed long‐term diastolic dysfunction and a diminished systolic strain response under stress in the mTBI group. At the molecular level, cardiac T‐p38MAPK and troponin I expression was pathologic modified post‐mTBI. We found linear correlations between brain sO2 measured immediately post‐mTBI and long‐term cardiac strain after 8 months. We report that initial cerebrovascular hypoxia and chronic cardiac dysfunction correlated with long‐term behavioral changes hinting at anxiety‐like and memory maladaptation. Conclusion Experimental juvenile mTBI induces time‐dependent cardiac dysfunction that corresponds to the initial neurovascular sO2 dip and is associated with long‐term behavioral modifications. These imaging biomarkers of the heart–brain axis could be applied to improve clinical pediatric mTBI management.
Introduction: Progression to heart failure is a known consequence of longstanding hypertrophic cardiomyopathy (HCM); however, routine function markers such as ejection fraction (EF) are often inadequate to predict dysfunction progression. The objective of this abstract was to create a novel metric, the Hybrid Strain Index (HSI), that can provide better characterization of heart failure progression. We hypothesized that longitudinal changes in a mouse model with known cardiac dysfunction could be more accurately differentiated with HSI than EF. Methods: Longitudinal 4D ultrasound (4DUS) data from mice with hypertrophic cardiomyopathy secondary to cardiac deletion of the carnitine palmitoyltransferase 2 enzyme ( Cpt2 M-/- ; n=12) and littermate controls (n=14) were analyzed using a custom MATLAB toolbox that derived both global volumetric (e.g., EF) and regional kinematic (e.g., circumferential and longitudinal strain) measurements. The circumferential and longitudinal regions most sensitive to disease progression were identified as the base (E θθ ) and posterior-wall (E LL ), respectively. The HSI metric was then calculated as the L2 norm of those peak-strain values. Results: To identify the earliest age of deviation between Cpt2 M-/- and controls, 95% confidence intervals from linear regression through HSI values intersected at 5.7 weeks old, compared to 7.1 weeks old using EF, suggesting HSI provides earlier sensitivity to cardiac dysfunction. Additionally, area-under-curve (AUC) measurements from ROC analysis of each metric, regardless of age, showed greater differentiation between cohorts using HSI (AUC = 0.91) than EF (AUC = 0.84). This further suggests enhanced diagnostic value of HSI compared to EF in the setting of cardiac dysfunction. Conclusions: The proposed HSI metric demonstrated greater sensitivity to detecting cardiac dysfunction and disease progression, compared to EF, in a mouse model of hypertrophic cardiomyopathy ( Cpt2 M-/- ).
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