Abstract 16976: Derangements in Cardiac Oxidative Metabolism in Humans With Dilated Cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is associated with impaired myocardial perfusion reserve and impaired myocardial oxidative metabolism. However, the association between myocardial perfusion reserve and oxidative metabolism, is not fully understood. Hypothesis: Reduced myocardial perfusion reserve is associated with reduced myocardial oxidative metabolism. Methods: Using non-invasive cardiac imaging, we studied 8 DCM patients and 14 normal subjects. Myocardial perfusion reserve index (MPRI) was calculated using cardiac magnetic resonance as the normalized rate of myocardial signal augmentation following gadolinium contrast injection between rest and regadenoson induced stress. Resting oxidative metabolism was calculated as the myocardial mono-exponential decay rate (Kmono) of [ 11 C]acetate by positron emission tomography normalized per unit demand (rate-pressure product, RPP) (Kmono/RPP). Results: MPRI was lower in DCM compared to controls (1.25 ± 0.22 vs 1.59 ± 0.49, p=0.038). Similarly, Kmono/RPP was lower in DCM compared with normal subjects (0.6x10e-3 ± 0.15 x10e-3 vs 1.2x10e-3 ± 0.9x10e-3, p<0.0001). There was a linear relation between Kmono and RPP in normal subjects. However, DCM patients showed no increase in Kmono regardless of RPP (Figure 1A). Kmono/RPP was not significantly related to MPRI in either group (Figure 1B). Conclusions: Patients with DCM exhibit markedly impaired myocardial oxidative metabolism compared to normal subjects. However, this impairment was not quantitatively related to impaired myocardial perfusion reserve. Of the various mechanisms that could explain decrease in oxidative metabolism in DCM, these data suggest that reduced myocardial perfusion is not the principal driver of impaired oxidative metabolism.

Targeted Deletion of Interleukin-6 in a Mouse Model of Chronic Inflammation Demonstrates Opposing Roles in Aging: Benefit and Harm

Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.