The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

Background-Heart failure with preserved ejection fraction (HF-nlEF) is common in aged individuals with systolic hypertension and is frequently ascribed to diastolic dysfunction. We hypothesized that such patients also display combined ventricular-systolic and arterial stiffening that can exacerbate blood pressure lability and diastolic dysfunction under stress. Methods and Results-Left ventricular pressure-volume relations were measured in patients with HF-nlEF (nϭ10) and contrasted with asymptomatic age-matched (nϭ9) and young (nϭ14) normotensives and age-and blood pressurematched controls (nϭ25). End-systolic elastance (stiffness) was higher in patients with HF-nlEF (4.7Ϯ1.5 mm Hg/mL) than in controls (2.1Ϯ0.9 mm Hg/mL for normotensives and 3.3Ϯ1.0 mm Hg/mL for hypertensives; PϽ0.001).Effective arterial elastance was also higher (2.6Ϯ0.5 versus 1.9Ϯ0.5 mm Hg/mL) due to reduced total arterial compliance; the latter inversely correlated with end-systolic elastance (Pϭ0.0001). Body size and stroke volumes were similar and could not explain differences in ventricular-arterial stiffening. HF-nlEF patients also displayed diastolic abnormalities, including higher left ventricular end-diastolic pressures (24.3Ϯ4.6 versus 12.9Ϯ5.5 mm Hg), caused by an upward-shifted diastolic pressure-volume curve. However, isovolumic relaxation and the early-to-late filling ratio were similar in age-and blood pressure-matched controls. Ventricular-arterial stiffening amplified stress-induced hypertension, which worsened diastolic function, and predicted higher cardiac energy costs to provide reserve output. Conclusion-Patients

The E(es) can be reliably estimated from simple noninvasive measurements. This approach should broaden the clinical applicability of this useful parameter for assessing systolic function, therapeutic response and ventricular-arterial interaction.

Background-Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. Methods and Results-Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures Ͼ60 mm Hg and systolic pressures Ͼ140 mm Hg to once-daily ALT-711 (210 mg; nϭ62) or placebo (nϭ31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (Ϫ5.3 versus Ϫ0.6 mm Hg at day 56; Pϭ0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (Pϭ0.056). Mean pressure declined similarly in both groups (Ϫ4 mm Hg; PϽ0.01 for each group, Pϭ0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711-treated subjects versus no change with placebo (Pϭ0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (PϽ0.05 at day 56, Pϭ0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group. Conclusions-ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.