BackgroundThere is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis.MethodsIn this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160 mg/m2/day for six cycles of 1 week on and 1 week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440).FindingsBetween Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160 mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)].After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10 mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40 mg/m2/day cohort, and improved in one patient by 3 points in the 160 mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10 mg/m2/day cohort, and improved in one patient in the 40 mg/m2/day cohort.InterpretationThis study showed that administration of 10 or 40 mg/m2/day intravenous PRI-724 over 12 weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160 mg/m2/day cohort.Funding SourceAMED.

Isovolumic contractions were imposed by intraventricular balloon in 39 isolated, blood-perfused canine hearts to investigate the effects of myocardial stretch on contractile force. After stabilization at 37°C, left ventricular volume was increased so that end-diastolic pressure increased from 0 to 5 mmHg. After the immediate increase in developed pressure [DP; from 37 ± 14 to 82 ± 22 mmHg (means ± SD)], there was a slow secondary rise in DP (97 ± 27 mmHg) that peaked at 3 min. However, DP subsequently decreased over the next 7 min back to the initial value (84 ± 25 mmHg). Light emission from macroinjected aequorin ( n = 10 hearts) showed that changes in intracellular calcium [3 min: 124 ± 15% ( P < 0.01); 10 min: 99 ± 18% of baseline] paralleled DP changes. Increases in myocardial adenosine 3′,5′-cyclic monophosphate (cAMP) content ( n = 12) accompanied the secondary rise in DP. In contrast, the gradual elevation of DP after the stretch was not exerted during continuous β-adrenergic stimulation by isoproterenol. Thus, in contrast to isolated muscle, stretch only transiently increases intracellular calcium and contractile strength in intact hearts. The findings of changes in cAMP and abolition of the phenomena by β-stimulation suggest that a primary stretch-mediated influence on cAMP metabolism may underlie these phenomena.

We evaluated dynamic effects of the carotid sinus baroreflex on ventriculoarterial coupling. In seven anesthetized, vagotomized dogs, we bilaterally isolated carotid sinuses and randomly changed carotid sinus pressure while measuring aortic pressure, aortic flow, and left ventricular pressure. Estimating left ventricular end-systolic elastance (E.) and effective arterial elastance (Ea) on a beat-to-beat basis, we determined transfer functions from the carotid sinus pressure to Ees (HE,,) Figure 1 illustrates the basic framework of the ventriculoarterial coupling in the pressure-volume plane. End-systolic elastance (Ees), which represents contractility of the left ventricle, is the slope of the end-systolic pressure-volume relation (line A in Figure 1). Effective arterial elastance (Ea), which in the steady state approximates arterial resistance divided by the cardiac cycle length, is the slope of the end-systolic pressure-stroke volume relation (line B in Figure 1). Increases in Ea reflect increases in arterial resistance or heart rate. The end-systolic equilibrium point that re-

Shimizu, Juichiro, Koji Todaka, and Daniel Burkhoff. Load dependence of ventricular performance explained by model of calcium-myofilament interactions. Am J Physiol Heart Circ Physiol 282: H1081-H1091, 2002; 10.1152/ ajpheart.00498.2001.-Although a simple concept of loadindependent behavior of the intact heart evolved from early studies of isolated, intact blood-perfused hearts, more recent studies showed that, as in isolated muscle, the mode of contraction (isovolumic vs. ejection) impacts on end-systolic elastance. The purpose of the present study was to test whether a four-state model of myofilament interactions with length-dependent rate constants could explain the complex contractile behavior of the intact, ejecting heart. Studies were performed in isolated, blood-perfused canine hearts with intracellular calcium transients measured by macroinjected aequorin. Measured calcium transients were used as the driving function for the model, and length-dependent rate constants yielding the highest concordance between measured and model-predicted midwall stress at different isovolumic volumes were determined. These length-dependent rate constants successfully predicted contractile behavior on ejecting contractions. This, along with additional model analysis, suggests that length-dependent changes in calcium binding affinity may not be an important factor contributing to load-dependent contractile performance in the intact heart under physiological conditions. left ventricle; calcium transient; four-state model; excitationcontraction coupling ALTHOUGH MANY EARLY STUDIES of isolated cardiac muscle showed a complex dependence of myocardial contractile force on length, rate, and extent of shortening, a simpler concept of load-independent behavior of the intact heart initially evolved from studies in isolated, intact blood-perfused hearts. These studies led to widespread acceptance of the end-systolic pressure-volume relationship (ESPVR) as a load-independent index of ventricular contractile state (29). Although the ESPVR approach has proven invaluable as a tool to quantify and track changes in ventricular contractile state under a wide range of conditions and has enabled new understanding of ventricular-vascular coupling, it is a phenomenological description of ventricular properties with no link to basic mechanisms of myofilament contraction. Additionally, it has become increasingly clear that loading conditions can influence the ESPVR (6, 7, 15).Attempting to establish a link between the growing understanding of the biochemical interactions involved in muscle contraction and whole organ properties, we demonstrated the feasibility of a four-state biochemical scheme of calcium, actin, and myosin interactions (Fig. 1) to explain the complex contractile behavior of the intact heart under isovolumic conditions at different volumes (3,5). Initial modeling studies led to experiments focused on characterizing length dependence of myocardial calcium sensitivity in intact hearts (28). We identified important quantitative dif...

No abstract