No abstract

The behavior of the end-systolic ventricular diameter was examined during control state, atrial pacing, and acute volume loading (VL) followed by methoxamine infusion in conscious dogs instrumented with a left ventricular micromanometer and ultrasonic crystals measuring internal diameter and wall thickness. Heart rate and systolic pressure were markedly increased by maximal VL but for moderate VL were minimally modified. Moderate VL increased end-diastolic diameter by 5% and end-systolic diameter by 2.9% with a significant increase of systolic stress. There was no common final pathway of shortening in the force-velocity-length diagram for different preloads. During methoxamine infusion, the end-systolic pressure-diameter points described a linear regression but points obtained during atrial pacing before VL were significantly shorter. We conclude that VL increases the total loading of the heart producing a lengthening of the end-systolic diameter when end-diastolic diameter is increased. This reduces the expression of the Starling mechanism and suggests caution when interpreting end-systolic pressure-diameter relations and derived indices for significantly different end-diastolic diameters.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy. This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1β, IL-6, TNF-α and OSM), T-reg-related cytokines (IL-10 and TGF-β), Th1-related cytokine (IFN-γ), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR. Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 (p = .04) and IL-23 (p = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 (p = .02), BD-2 (p = .02), IL-1β (p = .004) and OSM (p = .02) in the rash zone were associated with longer progression-free survival. Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.

The very early left ventricular response to chronic volume overload induced by aortic insufficiency (AI) was examined in conscious dogs previously instrumented with a left ventricular micromanometer and ultrasonic crystals measuring internal diameter, segmental length, and parietal wall thickness. Acute volume loading with dextran (AVL) was compared with that 24 and 48 h after AI induced by a perforation of the aortic valve. beta-Blockade was also produced before and after AI. For a similar increase in preload in AVL and after AI, the percent change in systolic shortening of diameters and segments (% delta L) increased from 30.4 to 34.1% after AI (P less than 0.01). For matched calculated wall stress during AVL and AI, % delta L and peak velocity of shortening were significantly increased after AI, and the same results were reproduced after beta-blockade. We conclude that, at the early phase of chronic volume overload before hypertrophy appears, left ventricular hyperfunction is mainly due to a nonsympathetic increased contractility and that, in the conscious dog, the inotropic state appears to be modified by a sustained increased preload.