G. Ambrosio

Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes

OBJECTIVE To investigate the contribution of apoptosis in the development of the skeletal myopathy in chronic heart failure. DESIGN The electrophoretic pattern of myosin heavy chains (MHC), fibre cross sectional area, number of in situ nick end labelling (TUNEL) positive apoptotic myocyte nuclei, and the tissue levels of caspase-3, Bcl-2, and ubiquitin were determined in biopsies taken from the vastus lateralis muscle. The study involved nine patients with severe chronic heart failure caused by ischaemic heart disease and hibernating myocardium and five controls. RESULTS In chronic heart failure patients the vastus lateralis showed a significant increase of MHC2a and MHC2b and a greater degree of fibre atrophy, as demonstrated by the decreased cross sectional area. There was also an increased number of TUNEL positive apoptotic myocyte nuclei. Tissue concentrations of Bcl-2 were decreased, while those of caspase-3 and ubiquitin were increased. Peak oxygen consumption (Vo 2) was negatively correlated with the number of TUNEL positive nuclei and the fibre cross sectional area. There was a correlation between the number of apoptotic nuclei and the fibre cross sectional area, but no correlation between myosin heavy chains and number of apoptotic nuclei. CONCLUSIONS Myocyte apoptosis occurs in the skeletal muscle of patients with chronic heart failure, and its magnitude is associated with the severity of exercise capacity limitation and the degree of muscle atrophy. Muscle atrophy contributes to the limitation of exercise capacity, together with the increased synthesis of fast, more fatiguable myosin heavy chains.

Current presentation and management of heart failure in cardiology and internal medicine hospital units: a tale of two worlds--the TEMISTOCLE study.

BACKGROUND The purpose pf the current article is to describe the clinical profile, use of resources, management and outcome in a population of real-world inpatients with heart failure. METHODS AND RESULTS With a prospective, cross-sectional survey on acute hospital admissions, we evaluated the overall and provider-related differences in patient characteristics, diagnostic work-up, treatment and inhospital outcome of 2127 patients with heart failure admitted to 167 cardiology departments and 250 internal medicine departments between February 14 and 25, 2000. Patients admitted to cardiology units were younger (56.3% >70 years vs 76.2%, P <.0001), had more severe symptoms (NYHA IV 35% vs 29%, P =.00014), and more often underwent evaluation of ventricular function (89.3% vs 54.8%, P <.0001) and coronary angiography (7.5% vs 0.9%, P <.0001) than those admitted to medical units. Moreover, they were more often prescribed beta-blockers (17.8% vs 8.7%, P <.0001). However, prescription of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (78.7% vs 81.5%, P = not significant [NS]) and inhospital mortality (5.2% vs 5.9%, P = NS) were similar. A 6-month follow-up visit was performed in 56.4% of cases (68.2% of cardiology vs 49.4% of medicine patients, P <.0001); 6-month readmission (43.7% vs 45.4%, P = NS) and mortality (13.9% vs 16.7%, P = NS) rates were similar. CONCLUSIONS Patients with heart failure admitted to cardiology and internal medicine units represent 2 clearly different populations. In both groups, diagnostic procedures and evidence-based treatments, such as beta-blockers, appeared to be underused, and there was a lack of structured follow-up, as well as a poor 6-month prognosis.

Magnet RaD for the US LHC Accelerator Research Program (LARP)

TUA2OR6 Magnet RD fax: 510-486-5310; e-mail: sagourlay@lbl.gov). G. Ambrosio, N. Andreev, E. Barzi, R. Bossert, V. S. Kashikhin, V. V. Kashikhin, F. Nobrega, I. Novitsky, D. Turrioni, R. Yamada, and A.V. Zlobin are with Fermilab National Accelerator Laboratory, Batavia, IL 3 M. Anerella, A. Ghosh , , R. Gupta, M. Harrison, J. Schmazle, and P. Wanderer are with Brookhaven National Laboratory, Upton, NY.

Beneficial Effects on Skeletal Muscle of the Angiotensin II Type 1 Receptor Blocker Irbesartan in Experimental Heart Failure

BackgroundIn congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-&agr; (TNF&agr;). Angiotensin II receptors are thought to play a role in controlling apoptosis. We tested the hypothesis that angiotensin II receptor blockade could prevent skeletal muscle apoptosis in rats with CHF. Methods and ResultsCHF was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten additional animals were injected with saline and acted as controls. After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg · kg−1 · d−1 irbesartan through osmotic minipumps, and 10 of the 36 rats were treated with 2 mg · kg−1 · d−1 nifedipine in drinking water. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspases 3 and 9 were determined, as were plasma levels of TNF&agr; and angiotensin II. Myocyte apoptosis and muscle atrophy were significantly decreased with irbesartan compared with untreated CHF rats. Irbesartan-treated rats had fewer cells labeled positively with terminal deoxynucleotidal transferase-mediated dUTP nick-end labeling and fewer caspases; however, they also had increased Bcl-2 levels and muscle fiber cross-sectional areas. The MHC pattern in irbesartan-treated animals was similar to that in controls. Nifedipine animals behaved like the untreated CHF animals. Angiotensin II was increased 3- to 4-fold in all CHF rats (treated and untreated). TNF&agr; levels were decreased in irbesartan-treated rats but not in nifedipine-treated rats. ConclusionsAngiotensin II receptor blockade can protect from the development of apoptosis-dependent atrophy and from changes in MHCs. The reduction of TNF&agr; may play a role in this process.

Skeletal muscle myosin heavy chain expression in rats with monocrotaline-induced cardiac hypertrophy and failure. Relation to blood flow and degree of muscle atrophy

BACKGROUND In congestive heart failure (CHF) the skeletal muscle of the lower limbs develops a myopathy characterised by atrophy and shift from the slow to the fast type fibres. The mechanisms responsible for these changes are not clear yet. OBJECTIVES We investigated the influence of blood flow and degree of muscle atrophy on the myosin heavy chains (MHC) composition of the soleus and extensor digitorum longus (EDL) of rats with right ventricle hypertrophy and failure. METHODS CHF was induced in 16 rats by injecting 30 mg/kg monocrotaline. Eight animals had the same dose of monocrotaline but resulting in compensated right ventricle hypertrophy. Two age- and diet-matched groups of control animals (nine and five respectively) were also studied. The relative percentage of MHC1 (slow isoform), MHC2a (fast oxidative) and MHC2b (fast glycolytic) was determined by densitometric scan after electrophoretic separation. The relative weights of soleus and EDL (muscle weight/body weight) were taken as an index of muscle atrophy. Skeletal muscle blood flow was measured by injecting fluorescent micropheres. RESULTS CHF and Control (Con) rats showed similar degree of atrophy both in soleus (0.40 +/- 0.06 vs. 0.44 +/- 0.06 p = NS), and EDL (0.47 +/- 0.04 vs. 0.45 +/- 0.02, p = 0.09). In CHF rats these two muscles showed a statistically significant MHCs redistribution toward the fast type isozymes. In fact in EDL of CHF rats MHC2a was 30.5 +/- 6.1% vs. 35.8 +/- 8.6% of the Con (p < 0.05). MHC2b was however higher (68.5 +/- 6.6% vs. 61.0 +/- 9.6%, p = 0.017). In the soleus of CHF rats MHC1 was decreased (87.6 +/- 3.4% vs. 91.9 +/- 5.2%, p = 0.02), while MHC2a was increased (12.04 +/- 3.5% vs. 7.9 +/- 5.2%; p = 0.028). Similar changes were not found in the muscles of the compensated hypertrophy animals. No correlation was found between MHC pattern and the relative muscle weight in the CHF animals. Soleus blood flow in CHF rats was significantly lower than that of Con (0.11 +/- 0.03 ml/min/g vs. 0.22 +/- 0.03 p < 0.05), while no differences were found in EDL (0.06 +/- 0.02 ml/min/g vs. 0.08 +/- 0.02, p = NS). CONCLUSIONS In rats with CHF a skeletal muscle myopathy characterised by a shift of the MHCs toward the fast type isoforms occurs. The magnitude of the shift correlates neither with the degree of atrophy, nor with the skeletal muscle blood flow, suggesting that these two factors do not play a pivotal role in the pathogenesis of the myopathy.

A First Baseline for the Magnets in the High Luminosity LHC Insertion Regions

The High Luminosity LHC (HL-LHC) project aims at accumulating 3000 fb-1 in the years 2023-2035, i.e., ten times more w.r.t. the nominal LHC performance expected for 2010-2021. One key element to reach this challenging performance is a new insertion region to reduce the beam size in the interaction point by approximately a factor two. This requires larger aperture magnets in the region spanning from the interaction point to the matching section quadrupoles. This aperture has been fixed to 150 mm for the inner triplet quadrupoles in 2012. In this paper, we give a first baseline of the interaction region. We discuss the main motivations that lead us to choose the technology, the combination of fields/gradients and lengths, the apertures, the quantity of superconductor, and the operational margin. Key elements are also the constraints given by the energy deposition in terms of heat load and radiation damage; we present the main features related to shielding and heat removal.

Skeletal muscle myosin heavy chains in heart failureCorrelation between magnitude of the isozyme shift, exercise capacity, and gas exchange measurements

BACKGROUND Patients with congestive heart failure (CHF) have a reduced exercise capacity because of the early appearance of fatigue and dyspnea. Qualitative changes in the skeletal muscle composition and metabolism can be responsible for the origin of symptoms METHODS We correlated the myosin heavy chain (MHC) composition of the gastrocnemius in 20 patients with different degrees of CHF to NYHA class, diuretic consumption, echocardiographic parameters, and expiratory gases measured during cardiopulmonary exercise testing. MHC composition was determined electrophoretically in skeletal muscle needle microbiopsies and the percent distribution was calculated by densitometry. Maximal cardiopulmonary exercise testing was performed on a treadmill with a modified Naughton protocol. A capnograph was used. RESULTS There was no correlation between ejection fraction, left ventricular end systolic diameter, left ventricular end diastolic diameter, and MHC composition. We found a significant positive correlation between the percentage of MHC 1 (slow aerobic isoform) and NYHA class (r2 = 0.62, p < 0.0001), peak VO2 (r2 = 0.5, p < 0.0004), ventilatory threshold (VT) (r2 = 0.33, p = 0.008) and O2 pulse (peak VO2/HR) (r2 = 0.40, p = 0.003). There was a negative correlation between both MHC2a (fast oxidative) and MHC2b (fast glycolytic) with peak VO2 (r2 = 0.38, p = 0.004 and r2 = 0.37, p = 0.004, respectively), VT (r2 = 0.2, p = 0.046 and r2 = 0.34, p = 0.007, respectively), and O2 pulse (peak VO2/HR) (r2 = 0.39, p = 0.003 and r2 = 0.23, p = 0.03). NYHA class was also correlated positively with MHC2a and MHC2b (r2 = 0.46, p = 0.001 and r2 = 0.41, p < 0.006, respectively) and negatively with the same clinical and functional parameters. CONCLUSIONS The correlation between the magnitude of the MHC shift from the slow aerobic to the fast glycolytic and fast oxidative with both functional and objective measurements of exercise capacity (peak VO2, VT, O2 pulse) seem to suggest that changes in skeletal muscle composition may play a determining role in exercise tolerance in patients with CHF.

Design Studies for the Low-Beta Quadrupoles for the LHC Luminosity Upgrade

In this paper, we outline the present status of the design studies for the high-luminosity Large Hadron Collider, focusing on the choice of the aperture of the inner triplet quadrupoles. After reviewing some critical aspects of the design such as energy deposition, shielding, heat load, and protection, we present the main tentative parameters for building a 150-mm-aperture Nb3Sn quadrupole, based on the experience gathered by the LARP program in the past several years.

R&D of Nb/sub 3/Sn accelerator magnets at Fermilab

Fermilab is developing and investigating different high-field magnets (HFM) for present and future accelerators. The HFM R&D program focused on the 10-12 T magnets based on Nb/sub 3/Sn superconductor and explored both basic magnet technologies for brittle superconductors-wind-and-react and react-and-wind. Magnet design studies in support of LHC upgrades and VLHC were conducted. A series of 1-m long cos-theta dipole models based on the wind-and-react technique was fabricated and tested. Three 1-m long flat racetracks and the common coil dipole model, based on a single-layer coil and react-and-wind technique, were also fabricated and tested. Extensive theoretical and experimental studies of electro-magnetic instabilities in Nb/sub 3/Sn strands, cables and magnets were performed and led to a successful 10 T dipole model. This paper presents the details of Fermilabs HFM program, reports its status and major results, and formulates the next steps for the program.

Test Results of the First 3.7 m Long Nb3Sn Quadrupole by LARP and Future Plans

In December 2009 during its first cold test, LQS01, the first Long Nb3Sn Quadrupole made by LARP (LHC Accelerator Research Program, a collaboration of BNL, FNAL, LBNL and SLAC), reached its target field gradient of 200 T/m. This target was set in 2005 by the US Department of Energy, CERN and LARP, as a significant milestone toward the development of Nb3Sn quadrupoles for possible use in LHC luminosity upgrades. LQS01 is a 90 mm aperture, 3.7 m long quadrupole using Nb3Sn coils. The coil layout is equal to the layout used in the LARP Technological Quadrupoles (TQC and TQS models). Pre-stress and support are provided by a segmented aluminum shell pre-loaded using bladders and keys, similarly to the TQS models. After the first test the magnet was disassembled, reassembled with an optimized pre-stress, and reached 222 T/m at 4.5 K. In this paper we present the results of both tests and the next steps of the Long Quadrupole R&D.