Mitochondria are critical for neuronal function and must be reliably distributed through complex neuronal architectures. By quantifying in vivo mitochondrial transport and localization patterns in the dendrites of Drosophila visual system neurons, we show that mitochondria make up a dynamic system at steady-state, with significant transport of individual mitochondria within a stable global pattern. Mitochondrial motility patterns are unaffected by visual input, suggesting that neuronal activity does not directly regulate mitochondrial localization in vivo. Instead, we present a mathematical model in which four simple scaling rules enable the robust self-organization of the mitochondrial population. Experimental measurements of dendrite morphology validate key model predictions: to maintain equitable distribution of mitochondria across asymmetrically branched subtrees, dendritic branch points obey a parent-daughter power law that preserves cross-sectional area, and thicker trunks support proportionally bushier subtrees. Altogether, we propose that ″housekeeping″ requirements, including the need to maintain steady-state mitochondrial distributions, impose constraints on neuronal architecture.

Introduction: For Marfan syndrome patients (MFS) with thoracic aortic aneurysms (TAA), prosthetic graft surgery provides lifesaving benefits, but adverse event risk persists in the native aorta for which mechanism is unclear. Sustained impact of proximal grafts on biomechanics within and distal to grafts is unknown. Methods: MFS patients with chronic (> 6 month) proximal grafts were compared to non-surgical MFS (nsMFS) and age/sex matched controls: Wall shear stress (WSS) on 4D flow cardiac MRI and size (diameter) were quantified at aortic landmarks (ascending, arch, descending, thoracoabdominal). Results: 34 subjects were studied including MFS late (7.3±6.7 years) after graft implantation (n=12). Post-surgical MFS were of similar age (p=0.93) and sex (p=0.64) to controls but older than non-surgical MFS (45±10 vs 33±11 yo, p=0.01): In the ascending aorta (grafted territory), post-surgical MFS had higher WSS (1.17±0.55 Pa) than nsMFS (0.74±0.17 Pa) and controls (0.60±0.17 Pa; p=0.002 for trend). Similarly, in the (native) descending aorta, WSS was higher in post-surgical (1.06±0.24 Pa) than nsMFS (0.97±0.11) and controls (0.83±0.16; p=0.02) ( Figure ) paralleling results in the arch (p=0.06) and a similar trend in the thoracoabdominal aorta (p=0.12). Among the overall MFS cohort (n=23), proximal graft implantation associated with increased WSS in the ascending and descending aorta (both p<0.01) in analyses controlling for age and aortic size in respective territories ( Table ). Conclusions: Prosthetic grafts yield sustained alterations in aortic biomechanics, including elevated WSS (a marker of adverse remodeling) in grafted regions and the distal native aorta.

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Background: Prosthetic graft replacement of thoracic aortic aneurysms (TAA) yields benefits but risks persist in the native aorta, especially in Marfan syndrome (MFS). Differential biomechanics between chronically grafted and native aortic regions are unknown. Methods: Functional cardiac magnetic resonance (cine-CMR) imaging was performed in non-surgical MFS patients (root or ascending diameter≤4.5cm) and patients after (>1 year) proximal grafting. Analyses included mid-ascending and -descending aortic size (diameter, area) and compliance indices, including global circumferential strain (GCS), fractional area change (FAC), stiffness index, and distensibility. Results: 46 MFS patients underwent cine-CMR, including 21 with chronic proximal grafts (10.5 +/- 7.3 years post-operatively). Patients with and without grafts had similar clinical and hemodynamic characteristics. Grafted and non-grafted ascending aortic size was similar between groups (p=NS), but functional parameters differed as evidenced by decrements in GCS, FAC, stiffness index, and distensibility (all p<0.001), consistent with prosthesis-associated reductions in compliance: Proximal grafts associated with decreased ascending aortic strain (B= -7.09, p<0.001) independent of age and aortic root size. Notably, native descending aortic size was larger in post-operative patients (p<0.01), paralleled by increased GCS (p<0.001) and decreased stiffness (p=0.04). In multivariate analysis, proximal grafts associated with increased descending aortic strain when controlling for ascending aortic area (B=4.19, p<0.001) or root size (B=3.14, p=0.045). Conclusions: Marfan syndrome patients with chronic proximal aortic grafts manifest distinct vessel wall biomechanics in grafted and native regions that differ from non-surgical comparators, including decreased strain (a marker of reduced compliance) within grafted territories and increased strain in native aortic regions distal to grafts.

e24070 Background: Cardiac metastases (CMET) can occur in late-stage cancer, but limited data exists on prognostic implications in context of current day cancer care. Cardiac magnetic resonance imaging (CMR) provides a new, well validated, means to identify CMET in vivo, and assess magnitude of lesion vascularity – which can vary in relation to tumor etiology and be compromised with tumor necrosis. Survivorship in pts with CMET and modifying impact of lesion vascularity are unknown. Methods: The population comprised adult (≥18yo) pts with metastatic cancer derived from a dual site CMR registry, including pts with and without CMET on CMR. CMR was performed via a uniform protocol for which CMET was defined using established criteria as a cardiac mass with late gadolinium enhancement; lesion vascularity was measured on perfusion-CMR. Cancer type was categorized by pathological review and follow-up was performed for all-cause mortality. Results: 330 pts (59±15 yo; 55% M) were studied, inclusive of CMET and controls matched for cancer etiology/stage. Among pts with CMET, cancer etiology varied (sarcoma 24% | GI 18% | GU 13% | lymphoma 13% | lung 10% | skin/melanoma 7% |); cases and controls were similar with respect to age, sex, anti-cancer regimen, and cardiac function on CMR (all p = NS). Median duration of post-CMR follow-up was 19 months [IQR 11.9 – 43.6]; 92% had clinical follow-up ≥ 1 year or mortality within this interval, including an aggregate 1-year mortality in pts with CMET of 53% (43% in CMET - controls; p = 0.09). Among cancer categories, pts with lymphoma were at decreased risk for death (HR 0.44 [0.26 – 0.75], p = 0.002); risk was increased in pts with GI malignancies (1.63 [1.12 – 2.37], p = 0.01) or those treated with antimetabolites or kinase inhibitors (both p < 0.05): Neither age, sex, cardiac risk factors nor function granted increased risk for death (all p = NS). Regarding Cmet tissue characteristics, decreased lesion perfusion conferred increased mortality risk irrespective of whether assessed as a continuous variable (HR 1.29 [1.08 – 1.56]) or via graded tertiles (HR 1.32 [1.05 – 1.66]) of hypoperfusion (both p < 0.05). Decreased CMET perfusion conferred increased mortality risk (1.30 [1.03 – 1.64], p = 0.03) independent of cancer type or anticancer regimen. Conclusions: Among systemic cancer pts with CMET, survivorship varies and nearly half are alive ≥1 year post cardiac MRI diagnosis. Prognosis in pts with CMET varies inversely to lesion perfusion, with low vascularity lesions conferring increased mortality risk.[Table: see text]