Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial

Background and Aims: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations. Methods: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Results: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% confidence interval 76%–83%, P < .001) and hs-cTnI by 41% (95% confidence interval 32%–49%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. N-Terminal pro-B-type natriuretic peptide reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. Conclusions: N-Terminal pro-B-type natriuretic peptide and hs-cTnI concentrations are associated with key variables in obstructive hypertrophic cardiomyopathy. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy

Response of ATPases in the osmoregulatory tissues of freshwater fish Oreochromis niloticus exposed to copper in increased salinity

PubMedID: 22922878An increase in salinity of freshwater can affect the physiology and metal uptake in fish. In the present study, Nile tilapia Oreochromis niloticus were exposed to copper (1. 0 mg/l) in increased salinities (2, 4, and 8 ppt) for 0, 1, 3, 7, and 14 days. Following the exposures, the activities of Na+/K+-ATPase, Mg2+-ATPase, and Ca2+-ATPase were measured in the gill, kidney, and intestine to evaluate the changes in osmoregulation of fish. Results showed that increases in salinity and Cu exposure of fish significantly altered the ATPase activities depending on the tissue type, salinity increase, and exposure durations. Salinity-alone exposures increased Na+/K+-ATPase activity and decreased Ca2+-ATPase activity. Na+/K+-ATPase activity decreased following Cu exposure in 2 and 4 ppt salinities, though the activity increased in 8 ppt salinity. Ca2+-ATPase activity decreased in the gill and intestine in all salinities, while the activity mostly increased in the kidney. However, there were great variations in Mg2+-ATPase activity following exposure to salinity alone and salinity+Cu combination. Cu accumulated in the gill and intestine following 14 days exposure and accumulation was negatively correlated with salinity increase. Data indicated that ATPases were highly sensitive to increases in salinity and Cu and might be a useful biomarker in ecotoxicological studies. However, data from salinity increased freshwaters should carefully be handled to see a clear picture on the effects of metals, as salinity affects both metal speciation and fish osmoregulation. © 2012 Springer Science+Business Media B.V.108T269, FEF2008YL15Acknowledgments This study was supported by the Scientific and Technical Research Council of Turkey (108T269) and Research Fund (FEF2008YL15) to Berna KULAC¸ from C¸ ukurova University

Molecular basis of binding and stability of curcumin in diamide-linked y-cyclodextrin dimers

Curcumin is a naturally occurring molecule with medicinal properties that is unstable in water, whose efficacy as a drug can potentially be enhanced by encapsulation inside a host molecule. In this work, the thermodynamics and mechanism of binding of curcumin to succinamide- and urea-linked γ-cyclodextrin (γ-CD) dimers in water are investigated by molecular dynamics simulations. The simulated binding constants of curcumin to succinamide- and urea-linked γ-CD dimers at 310 K are 11.3 × 10⁶ M ⁻¹ and 1.6 × 10⁶ M ⁻¹, respectively, matching well with previous experimental results of 8.7 × 10⁶ M ⁻¹ and 2.0 × 10⁶ M ⁻¹. The simulations reveal structural information about the encapsulation of curcumin inside the diamide-linked γ-CD dimers, with distinct qualitative differences observed for the two dimers. In particular, (1) the predominant orientation of curcumin inside the urea-linked γ-CD dimer is perpendicular to that in the succinamide-linked γ-CD dimer; (2) the magnitude of the angle between the planes of the cyclodextrins is larger for the succinamide-linked γ-CD dimer; and (3) curcumin exhibits greater configurational freedom inside the urea-linked γ-CD dimer. A consequence of some of these structural differences is that the dimer interior is more accessible to water in the succinamide-linked γ-CD dimer. These observations explain the higher stability and lower binding constant observed experimentally for curcumin in the urea-linked cyclodextrin γ-CD dimer compared with the succinamide-linked γ-CD dimer. More generally, the results demonstrate how stability and binding strength can be decoupled and thus separately optimized in host–guest systems used for drug delivery.Samuel J. Wallace, Tak W. Kee, and David M. Huan