Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

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Alteration in the mechanical properties of arteries occurs with aging and disease, and arterial stiffening is a key risk factor for subsequent cardiovascular events. Arterial stiffening is associated with the loss of functional elastic fibers and increased collagen content in the wall of large arteries. Arterial mechanical properties are controlled largely by the turnover and reorganization of key structural proteins and cells, a process termed growth and remodeling. Fibulin-5 (fbln5) is a microfibrillar protein that binds tropoelastin, interacts with integrins, and localizes to elastin fibers; tropoelastin and microfibrillar proteins constitute functional elastic fibers. We performed biaxial mechanical testing and confocal imaging of common carotid arteries (CCAs) from fibulin-5 null mice (fbln5 −/− ) and littermate controls (fbln5 +/+ ) to characterize the mechanical behavior and microstructural content of these arteries; mechanical testing data were fit to a fourfiber family constitutive model. We found that CCAs from fbln5 −/− mice exhibited lower in vivo axial stretch and lower in vivo stresses while maintaining a similar compliance over physiological pressures compared to littermate controls. Specifically, for fbln5 −/− the axial stretch λ = 1.41 ± 0.07, the circumferential stress σ θ = 101 ± 32 kPa, and the axial stress σ z = 74 ± 28 kPa; for fbln5 +/+ λ = 1.64 ± 0.03, σ θ = 194 ± 38 kPa, and σ z = 159 ± 29 kPa. Structurally, CCAs from fbln5 −/− mice lack distinct functional elastic fibers defined by the lamellar structure of alternating layers of smooth muscle cells and elastin sheets. These data suggest that structural differences in fbln5 −/− arteries correlate with significant differences in mechanical properties. Despite these significant differences fbln5 −/− CCAs exhibited nearly normal levels of cyclic strain over the cardiac cycle.

Four newly synthesized ether lipid esters of cidofovir (CDV), hexadecyloxypropyl-CDV (HDP-CDV), octadecyloxyethyl-CDV (ODE-CDV), oleyloxypropyl-CDV (OLP-CDV), and oleyloxyethyl-CDV (OLE-CDV), were found to have enhanced activities against vaccinia virus (VV) and cowpox virus (CV) in vitro compared to those of CDV. The compounds were administered orally and were evaluated for their efficacies against lethal CV or VV infections in mice. HDP-CDV, ODE-CDV, and OLE-CDV were effective at preventing mortality from CV infection when treatments were initiated 24 h after viral inoculation, but only HDP-CDV and ODE-CDV maintained efficacy when treatments were initiated as late as 72 h postinfection. Oral pretreatment with HDP-CDV and ODE-CDV were also effective when they were given 5, 3, or 1 day prior to inoculation with CV, even when each compound was administered as a single dose. Both HDP-CDV and ODE-CDV were also effective against VV infections when they were administered orally 24 or 48 h after infection. In animals treated with HDP-CDV or ODE-CDV, the titers of both CV and VV in the liver, spleen, and kidney were reduced 3 to 7 log 10 . In contrast, virus replication in the lungs was not significantly reduced. These data indicate that HDP-CDV or ODE-CDV given orally is as effective as CDV given parenterally for the treatment of experimental CV and VV infections and suggest that these compounds may be useful for the treatment of orthopoxvirus infections in humans.Orthopoxvirus diseases continue to pose challenges to researchers preparing for a bioterrorist release of biological weapons of mass destruction. Rapid diagnostics for smallpox and the development of effective antiviral chemotherapies are two essential components for national preparedness (16,17). The in vitro and in vivo activities of cidofovir (CDV) against orthopoxviruses are well documented (3,4,8,9,15,18,(20)(21)(22)(23)(24); however, its usefulness is limited by the requirement for intravenous administration and dose-limiting nephrotoxicity (14). Orally active compounds with prolonged therapeutic levels in blood and reduced toxicity would be desirable for mass distribution in response to an actual release of the smallpox virus.Results from earlier studies with acyclovir and ganciclovir showed that alkoxyalkyl esters of the monophosphates of ganciclovir or acyclovir have improved oral bioavailabilities compared to those of the unmodified parent compounds and are effective against cytomegalovirus and herpes simplex virus infections (13). To improve the oral bioavailability of CDV, a novel series of analogs were synthesized by esterification with long-chain alkoxyalkanols. Hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CDV (ODE-CDV) were synthesized and evaluated in vitro for their efficacies against cowpox virus (CV) and vaccinia virus (VV) infections. As reported previously (15), HDP-CDV had 50% effective concentrations (EC 50 s) of 0.52 and 0.62 M against CV and VV, respectively, whereas the EC 50 s of CDV were 42 and 31 M, respectively. ODE-CD...