Giorgio Vescovo

Skeletal muscle abnormalities in rats with experimentally induced heart hypertrophy and failure

Abstract.Background: In congestive heart failure (CHF), function and metabolism of skeletal muscles are abnormal. Aim: To evaluate whether the reduced oxidative capacity of skeletal muscles in CHF is due to impaired O2 utilisation. Methods: CHF was induced in rats by injecting 50 mg/Kg monocrotaline. Several animals received the same dose of monocrotaline but only compensated right ventricular hypertrophy and no sign of congestion resulted. Two age- and diet-matched groups of control animals were also studied. In soleus and extensor digitorum longus (EDL) muscles, we studied skeletal muscle blood flow, oxidative capacity and respiratory function of skinned muscle fibres. Results: In CHF, we observed a decrease of muscle blood flow (statistically significant in the soleus, p < 0.05 vs. controls). In compensated rats, a similar trend in blood flow was observed. In both soleus and EDL, a significant reduction of high energy phosphate and a shift of the redox potential towards accumulation of reducing equivalents were observed. The reduction of energy charge was not correlated to the decrease of blood flow. In skinned myofibres, the ratio of O2 utilised in the presence and in absence of ADP (an index of phoshorilating efficiency) was reduced from 8.9 ± 1.9 to 2.7 ± 0.2 (p < 0.001) and from 5.7 ± 1.0 to 2.0 ± 0.3 (p < 0.01) in soleus and EDL, respectively. Activity of the different complexes of respiratory chain was investigated by means of specific inhibitors, showing major abnormalities at the level of complex I. In fact, inhibition of VO2 by rotenone was decreased from 83.5 ± 3.2 to 36.4 ± 9.6 % (p < 0.005) and from 81.8 ± 6.1 to 38.2 ± 7.4 % (p < 0.005) in soleus and EDL, respectively. Conclusions: In rats with CHF, abnormalities of oxidative phosphorylation of muscles occur and complex I of the respiratory chain seem to be primarily affected. The metabolic alterations of skeletal muscles in CHF may be explained, at least in part, by an impaired O2 utilisation.

Effect of thalidomide on the skeletal muscle in experimental heart failure.

Tumour Necrosis Factor α (TNFα) has been shown to contribute to heart failure (CHF) progression.

Skeletal muscle response to exercise and treatment: another sibyl in the heart failure syndrome?

Congestive Heart Failure is a clinical syndrome delivery to skeletal muscle due to the reduced blood characterized by decreased exercise capacity due to flow and to capillary endothelial dysfunction or early appearance of fatigue and dyspnoea. Skeletal damage may cause a relative ischaemia, which the muscle in CHF undergoes profound changes leading muscle fibre may adapt to, by inducing the preferento the development of a specific skeletal myopathy tial synthesis of anaerobic myosin isoforms. Fibres that may explain the origin of these symptoms: ‘‘the atrophy may be however explained by the high levels muscle hypothesis’’ [1]. Dyspnoea can be caused by of apoptosis occurring in the skeletal muscle of an hyperventilatory response to exercise due to patients with CHF and in animal models of right exaggerated ergoreflex activity (afferents sensitive to ventricular failure [5,6]. The magnitude of apoptosis skeletal muscle work) [1]. Fatigue is associated with correlates strongly with the impairment of exercise early anaerobic metabolism and lactate accumulation. capacity (peak VO ) and the degree of fibres atrophy.

Apixaban versus Dalteparin for the Treatment of Acute Venous Thromboembolism in Patients with Cancer: The Caravaggio Study

International and national guidelines recommend low-molecular-weight heparin for the treatment of venous thromboembolism (VTE) in patients with cancer. The aim of the Caravaggio study is to assess whether oral apixaban is non-inferior to subcutaneous dalteparin for the treatment of acute proximal deep vein thrombosis and/or pulmonary embolism in patients with cancer. The study is an investigator-initiated, multi-national, prospective, randomized, open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial (NCT03045406). Consecutive patients are randomized to receive oral apixaban or subcutaneous dalteparin for 6 months. Apixaban is given at a dose of 10 mg twice daily for the first 7 days and then 5 mg twice daily; dalteparin is given at a dose of 200 IU/kg for the first month and then 150 IU/kg once daily. The primary outcome of the study is objectively confirmed recurrent VTE as assessed by a central independent adjudication committee unaware of study treatment allocation. The primary safety outcome is major bleeding defined according to the guidelines of the International Society of Thrombosis and Haemostasis. Assuming a 6-month incidence of the primary outcome of 7% with dalteparin and an upper limit of the two-sided 95% confidence interval of the hazard ratio below the pre-specified margin of 2.00, 1,168 patients will be randomized considering an up to 20% loss in total patient-years (β = 80%; α one-sided = 0.025). The Caravaggio study has the potential, along with other recently performed or on-going studies, to make less cumbersome the management of VTE in patients with cancer by replacing parenteral with oral anticoagulation.

What We are Learning from Real World Data on Rivaroxaban for the Treatment of VTE: An Overview

Rivaroxaban is one of most common used DOACs in the treatment of VTE. Rivaroxaban has been tested in a series of premarketing studies and after it has been used in non-interventional studies and in real life studies.All studies experienced that rivaroxaban shows relevant safety concerning main outcomes of VTE therapy as recurrent VTE and major bleedings, in particular in patients that show similar clinical characteristics to those selected for EINSTEIN studies. Suggested doses of rivaroxaban seem to be safe also in real life studies while non-conventional doses may be associated to increased rate of clinical complications as recurrent VTE and major bleedings. Rivaroxaban shows also good safety when used in real life studies in patients with clinical characteristics that differ from those of patients in the EINSTEIN studies.