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Background: This study assessed the feasibility of a 12-week program of exercise, with and without intramuscular testosterone supplementation, in male patients with chronic heart failure (CHF) and low testosterone status and collected preliminary data for key health outcomes. Methods: Male patients with CHF (n = 41, age 67.2 years, range 51-84 years) with mean ± SD testosterone levels of 10.7 ± 2.6 nmol/L (309 ± 76 ng/dL) were randomly allocated to exercise with testosterone or placebo groups. Feasibility was assessed in terms of recruitment, intervention compliance, and attrition. Outcomes included an incremental shuttle walk test, peak oxygen uptake, muscular strength, echocardiographic measures, N-terminal pro–brain natriuretic peptide, inflammatory markers, depression (Beck Depression Inventory), and health-related quality of life (Minnesota Living with Heart Failure Questionnaire and Medical Outcomes Study Short-Form). Results: Attrition was 30% but with 100% compliance to exercise and injections in patients who completed the study. Similar improvements in shuttle walk test (18% vs 19%), body mass (−1.3 kg vs −1.0 kg), and hand grip strength (2.1 kg vs 2.5 kg) from baseline were observed in both groups. The exercise with testosterone group showed improvements from baseline in peak oxygen uptake (P < .01), Beck Depression Inventory (P < .05), leg strength (P < .05), and several Medical Outcomes Study Short-Form quality of life domains (P < .05), which were generally not apparent in the exercise with placebo group. Echocardiographic measures, N-terminal pro–brain natriuretic peptide, and inflammatory markers were mostly unchanged. Conclusions: This study shows for the first time that testosterone supplementation during a program of exercise rehabilitation is feasible and can positively impact on a range of key health outcomes in elderly male patients with CHF who have a low testosterone status. [Copyright &y& Elsevier]

Abstract: We determined the calcium signalling pathways involved in the mechanisms of contraction of the vasoconstrictive agonists KCl, U46619 and PDBu in isolated human pulmonary arteries. The influence of gender, vessel diameter and age of the patients was also investigated. Human pulmonary arteries (n =86) were loaded in a wire myograph and maintained at a tension equivalent to the in vivo pressure of 17.5 mm Hg, bubbled with 95%O2/5%CO2 to maintain pH 7.4 in physiological saline solution (PSS). Cumulative concentration–response curves were obtained to KCl (100 μM–100 mM), U46619 (1 nM–1 μM) or PDBu (1 nM–1 μM), before or after a 30 min incubation with either the voltage-gated calcium channel (VGCC) blocker nifedipine (10 μM), the store-operated calcium channel (SOCC) blocker SK&F96365 (50 μM) or in calcium-free PSS (−Ca2+PSS). The KCl response was partially blocked in −Ca2+PSS and with nifedipine. The U46619 response was partially blocked in −Ca2+PSS and with nifedipine and SK&F96365. Incubation in −Ca2+PSS had no effect on the response to PDBu. Endothelial intact arteries responded significantly higher to U46619 than endothelial denuded arteries. This study demonstrates that KCl induces pulmonary vasoconstriction via activation of extracellular calcium entry through VGCCs, U46619 induces pulmonary vasoconstriction predominantly via activation of VGCCs and PDBu induces pulmonary vasoconstriction via a calcium-independent pathway. [Copyright &y& Elsevier]

Abstract: We determined the calcium signalling pathways involved in the mechanisms of contraction of the vasoconstrictive agonists KCl, U46619 and PDBu in isolated human mesenteric arteries. The influence of gender, vessel diameter and age of the patients was also investigated. Human mesenteric arteries (n =76) were loaded in a wire myograph and maintained at a tension equivalent to the in vivo pressure of 100mm Hg, bubbled with 95%O2/5%CO2 to maintain pH 7.4 in physiological saline solution (PSS). Cumulative concentration–response curves were obtained to KCl (100μM–100mM), U46619 (1nM–1μM) or PDBu (1nM–1μM), before or after a 30min incubation with either the voltage-gated calcium channel (VGCC) blocker nifedipine (10μM), the store-operated calcium channel (SOCC) blocker SK&F96365 (50μM) or in calcium-free PSS (−Ca2+PSS). The KCl response was abolished in −Ca2+PSS and with nifedipine. The U46619 response was partially blocked in −Ca2+PSS and with nifedipine and predominantly blocked by SK&F96365. Incubation in −Ca2+PSS had no effect on the response to PDBu. Arteries from male patients responded significantly higher to KCl than arteries from female patients. This study demonstrates that KCl induces mesenteric vasoconstriction via activation of VGCCs, U46619 induces mesenteric vasoconstriction via activation of SOCCs, but also VGCCs and PDBu induce mesenteric vasoconstriction via a calcium-independent pathway. [Copyright &y& Elsevier]

Aims Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. Main methods Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. Key findings Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. Significance An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis. [ABSTRACT FROM AUTHOR]

The effects of testosterone on cardiac electrophysiology are poorly described. In this study we report the effect of physiologic testosterone therapy in 2 cohorts of men, the first with stable coronary disease and the second with congestive heart failure. Testosterone reduced QT dispersion in the heart failure cohort; no other effects were observed. [Copyright &y& Elsevier]