The effects of recombinant human growth hormone on skin, muscle and nerve

This study has investigated the mechanism of growth hormone (GH) action in the skin and its innervation as well as in skeletal muscle. Two main issues have been addressed: (1) To what extent are GH effects on extrahepatic targets the result of direct actions of this hormone, or, indirect effects mediated by local production of insulin-like growth factor I (IGF-I)? (2) Can GH, acting either directly or indirectly, be regarded as a key mediator of neurotrophic functions? These issues have been examined using three approaches: i) Muscle biopsies were taken from adult growth hormone-deficient patients before and after six to twelve months of recombinant human growth hormone (r-hGH) treatment, as part of a double-blind placebo controlled clinical trial. These patients exhibit reductions in muscle bulk and strength which can be reversed with r-hGH treatment. Muscle fibre types and fibre size were examined by light microscopy for an influence of r-hGH therapy. IGF-I message was localised to muscle fibre cytoplasm and fibre-type specific mRNA was quantified by combined non-radioactive in situ hybridisation with computerised image analysis. Circulating IGF-I levels were also assayed, making it possible to compare morphological changes in muscle fibre size with changes in circulating and muscle-derived IGF-I. The results obtained are consistent with a direct effect of GH on skeletal muscle resulting in generation of IGF-I by the muscle fibres. However, the influence of circulating IGF-I could not be dismissed from this scheme. ii) The innervation, morphology and function of eccrine sweat glands was examined in GH-deficient subjects who display reduced sweating, in patients with acromegaly (a GH hypersecretory state with excessive sweating) and in control subjects. Pilocarpine iontophoresis sweat tests were used to assess changes in sweating. An increase in the cholinergic innervation accompanied restoration of sweat rates in r-hGH treated subjects, whilst acromegalics displayed hypertrophy of sweat glands and elevated sweat gland innervation. These data imply an effect of GH on the sweat glands with repercussions for their innervation. A GH-mediated influence on neurotrophic support to the sweat gland nerves can thus be envisaged. iii) Aged rats were utilised to investigate direct effects of r-hGH administration in the vicinity of the footpad eccrine sweat glands, with the aim of minimising the confounding influence of serum IGF-I. Ageing is a state of relative GH deficiency and sweat glands are believed to be targets for GH action. Further aged rats display reductions in sweat gland size and innervation. An immunohistochemical method was utilised to stain for nerves and neurotrophin receptor sites around sweat glands. Due to injection-induced inflammatory effects, the results from this study were not clear, aside from an increase in sweat gland acinar size on r-hGH administration and the demonstration of parallel alterations in neurotrophin receptor expression and periacinar nerve density. These results allow the hypothesis of a direct effect of GH on target tissues to be advanced, resulting in local generation of IGF-I and, perhaps, of other target-derived neurotrophic factors

A randomized controlled trial of listening to recorded music for heart failure patients. Study protocol

Aims. To describe a conceptual framework and to test the effectiveness of a recorded music-listening protocol on symptom burden and quality of life in heart failure (HF) patients. Background. Heart failure is an important public health problem. Many HF patients experience symptoms burden and poor quality of life, even with current improvements in pharmacological treatments. Recorded music listening has been shown to improve outcomes in cardiovascular patients, but it has never been tested on HF patients and with a specific music protocol and a randomized controlled trial methodology. Methods. This study is a multicenter blinded randomized controlled trial that will involve 150 patients. Eligible patients will have a diagnosis of HF, in New York Heart Association functional classification of I to III, and will be recruited from 3 large hospitals in Northern Italy. Patients will be randomly allocated in a 1:1 ratio to receive recorded music-listening intervention with or without standard care for 3 months. Data will be collected at baseline and at the end of the first, second, and third month during the intervention, and at 6 months for follow-up. The following variables will be collected from HF patients with validated protocols: quality of life (primary endpoint), use of emergency services, rehospitalization rates, all cause mortality, self-care, somatic symptoms, quality of sleep, anxiety and depression symptoms, and cognitive function. Discussion. This study will examine the effect of recorded music listening on HF patients and will inform clinical practice. If the findings are found to be positive, the protocol could be used as a tool for evidence-based applications of recorded music in HF patients. The framework developed in this study may be helpful for future research focused on the effects of music in HF patients

Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.

An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis

Exploring the relationship between β-adrenergic receptor kinase-1 and physical symptoms in heart failure

Background The relationship between physical heart failure (HF) symptoms and pathophysiological mechanisms is unclear. Objective To quantify the relationship between plasma β-adrenergic receptor kinase-1 (βARK1) and physical symptoms among adults with HF. Methods We performed a secondary analysis of data collected from two studies of adults with HF. Plasma βARK1 was quantified using an enzyme-linked immunosorbent assay. Physical symptoms were measured with the HF Somatic Perception Scale (HFSPS). Generalized linear modeling was used to quantify the relationship between βARK1 and HFSPS scores. Results The average age (n = 94) was 54.5 ± 13.1 years, 76.6% were male, and a majority (83.0%) had Class III or IV HF. βARK1 was significantly associated with HFSPS scores (β = 0.22 ± 0.10, p = 0.038), adjusting for other predictors of physical symptoms (model R2 = 0.250, F(7, 70) = 3.34, p = 0.004). Conclusions Higher βARK1 is associated with worse physical HF symptoms, pinpointing a potential pathophysiologic underpinning

vWF (red; A,D,G,J,M), fibrin (green; B,E,H,K,N), and co-localized (C,F,I,L,O) photomicrographs of the LV.

<p>Images are from wildtype (A-C), early HF (D-I), acute HF (J-L), and chronic HF (M-O) mice. vWF staining is present within endocardial cells (within presumptive Weibel-Palade bodies) in all groups and very prominently in early HF (D, F, inset, arrows). Fibrin staining is limited on the endocardial surface of wildtype mice (B) but increased in HF mice (E, H, K, N). Small thrombi positive for both fibrin and vWF are present on the endocardial surface in both acute and chronic HF. vWF staining is limited on the endocardial surface in chronic HF mice (M-O). Note the heterogeneity in muscle fiber size in HF mice (I, O). Scale bar in O is 145 μm for all panels, except inset (84 μm).</p

Hemodynamic measurements from wildtype (WT) and CREB_A133 mice during cardiac echocardiography.

<p>Fractional area change (FAC); fractional shortening (FS); left ventricular ejection fraction (LVEF); stroke volume (SV); cardiac output (CO); LV diastolic (d) and systolic (s) internal diameter (LVID).</p><p>*p<0.05 vs WT,</p><p>**p<0.01 vs WT,</p><p>***p<0.001 vs WT,</p><p>^#p<0.05 vs Acute HF,</p><p>^##p<0.01 vs Acute HF,</p><p>^###p<0.001 vs Acute HF.</p><p>Hemodynamic measurements from wildtype (WT) and CREB_A133 mice during cardiac echocardiography.</p