Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF

Aerosol delivery to ventilated newborn infants: historical challenges and new directions

There are several aerosolized drugs which have been used in the treatment of neonatal respiratory illnesses, such as bronchodilators, diuretics, and surfactants. Preclinical in vitro and in vivo studies identified a number of variables that affect aerosol efficiency, including particle size, aerosol flows, nebulizer choice, and placement. Nevertheless, an optimized aerosol drug delivery system for mechanically ventilated infants still does not exist. Increasing interest in this form of drug delivery requires more controlled and focused research of drug/device combinations appropriate for the neonatal population. In the present article, we review the research that has been conducted thus far and discuss the next steps in developing the optimal aerosol delivery system for use in mechanically ventilated neonates

Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

<p>Abstract</p> <p>Background</p> <p>Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on <it>in vivo</it> coronary conductance and <it>in vitro</it> coronary microvascular diameter in intact and castrated male swine.</p> <p>Methods</p> <p>Pigs received intracoronary infusions of physiologic levels (1–100 nM) of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM) of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels.</p> <p>Results</p> <p><it>In vivo</it>, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. <it>In vitro</it>, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males.</p> <p>Conclusions</p> <p>Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.</p

Signalosome-Regulated Serum Response Factor Phosphorylation Determining Myocyte Growth in Width Versus Length as a Therapeutic Target for Heart Failure

Background: Concentric and eccentric cardiac hypertrophy are associated with pressure and volume overload, respectively, in cardiovascular disease both conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetrical growth of the cardiac myocyte in mainly width or length, respectively. The molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood. Identification of the mechanisms governing asymmetrical myocyte growth could provide new therapeutic targets for the prevention or treatment of heart failure. Methods: Primary adult rat ventricular myocytes, adeno-associated virus (AAV)–mediated gene delivery in mice, and human tissue samples were used to define a regulatory pathway controlling pathological myocyte hypertrophy. Chromatin immunoprecipitation assays with sequencing and precision nuclear run-on sequencing were used to define a transcriptional mechanism. Results: We report that asymmetrical cardiac myocyte hypertrophy is modulated by SRF (serum response factor) phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes in vitro and in vivo. SRF Ser 103 phosphorylation is bidirectionally regulated by RSK3 (p90 ribosomal S6 kinase type 3) and PP2A (protein phosphatase 2A) at signalosomes organized by the scaffold protein mAKAPβ (muscle A-kinase anchoring protein β), such that increased SRF phosphorylation activates AP-1 (activator protein-1)-dependent enhancers that direct myocyte growth in width. AAV are used to express in vivo mAKAPβ-derived RSK3 and PP2A anchoring disruptor peptides that block the association of the enzymes with the mAKAPβ scaffold. Inhibition of RSK3 signaling prevents concentric cardiac remodeling induced by pressure overload, while inhibition of PP2A signaling prevents eccentric cardiac remodeling induced by myocardial infarction, in each case improving cardiac function. SRF Ser 103 phosphorylation is significantly decreased in dilated human hearts, supporting the notion that modulation of the mAKAPβ-SRF signalosome could be a new therapeutic approach for human heart failure. Conclusions: We have identified a new molecular switch, namely mAKAPβ signalosome–regulated SRF phosphorylation, that controls a transcriptional program responsible for modulating changes in cardiac myocyte morphology that occur secondary to pathological stressors. Complementary AAV-based gene therapies constitute rationally-designed strategies for a new translational modality for heart failure

Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal&nbsp;model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF

Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

To determine the association of somatic mutations in acute myeloid leukemia (AML) with risk of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), we retrospectively studied pre-transplant genetic profiles obtained from next generation sequencing of 26 genes in 112 adult AML patients who underwent alloHSCT. Univariable and multivariable regression analyses were used to assess the association between the presence of a pathogenic mutation and risk of relapse after alloHSCT. Eighty-six percent (96/112) of patients had at least 1 pathogenic mutation. Mutations in TP53, WT1, and FLT3-ITD were associated with an increased risk of relapse after alloHSCT (adjusted HR [aHR] 2.90, P = .009, aHR 2.51, P = .02, and aHR 1.83, P = .07, respectively). DNMT3A mutation in the absence of FLT3-ITD and NPM1 mutations was associated with a lower relapse risk (aHR 0.22, P = .04). Comparison of pre- and post-alloHSCT genetic profiles showed clonal evolution in 6/6 patients, including acquisition of actionable mutations in 4 patients. In summary, genetic profiling is useful for assessing relapse risk in AML patients undergoing alloHSCT, and may identify patients in need of strategies to reduce this risk. Clonal evolution is present at post-alloHSCT relapse and repeat genetic profiling may uncover acquired actionable mutations