Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure

BACKGROUND: Chronic heart failure is characterized by immune activation and increased circulating levels of cytokines. Whether humoral factors contribute to the peripheral manifestations of the heart failure syndrome, such as muscle atrophy and reduced physical work capacity, however, is not clear. METHODS: We measured circulating cytokines (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6)), their soluble receptors (sTNF-alpha RII, IL-6sR), markers of immune activation (C-reactive protein (CRP)), muscle mass, aerobic capacity and muscle strength in 10 patients with heart failure (mean +/- S.E.; 63 +/- 3 years) and 11 controls (70 +/- 3 years). RESULTS: Heart failure patients exhibited decreased aerobic capacity (P < 0.01) and leg muscle strength (P < 0.05). Reduced muscle strength persisted in heart failure patients after statistical adjustment for differences in skeletal muscle size. All inflammatory markers were increased in heart failure patients (P < or = 0.05 to P < 0.01) compared to controls, with the exception of TNF-alpha. Despite no group differences in TNF-alpha, higher concentrations of this cytokine were correlated to lower skeletal muscle mass in the combined study population (range of r-values: -0.436 to -0.545; P < 0.05 to P < 0.02), as were IL-6 levels (range of r-values: -0.438 to -0.443; P < 0.05). TNF-alpha, sTNF-alpha RII, IL-6 and CRP showed strong negative relationships to aerobic capacity (range of r-values: -0.579 to -0.751; P < 0.01 to P < 0.001). In addition, elevated levels of IL-6 and TNF-alpha were associated with reduced leg and forearm skeletal muscle strength (range of r-values: -0.440 to -0.674; P < 0.05 to P < 0.01). Finally, correlations between cytokines and functional measures were present when heart failure patients were analyzed separately (range of r-values: -0.646 to -0.673; P < 0.05). CONCLUSIONS: Our results suggest that circulating cytokines are related to both skeletal muscle mass and physical function. These findings provide further evidence to support the hypothesis that immune activation contributes to skeletal muscle atrophy and reduced functional capacity in heart failure patients.     

Resistant Hypertension and Undiagnosed Primary Hyperaldosteronism Detected by Use of a Computerized Database

J Clin Hypertens (Greenwich). 2011;13:487–491.©2011 Wiley Periodicals, Inc. A pharmacy database was used to identify patients with resistant hypertension who could then be tested for the presence of primary hyperaldosteronism. Inclusion criteria were: (1) resistant hypertension defined as uncontrolled hypertension and use of 3 antihypertensive medication classes or ≥4 antihypertensive classes regardless of blood pressure; (2) low or normal potassium levels (≤4.9 mEq/L); and (3) continuous health care from October 1, 2008, to February 28, 2009. Exclusion criteria were: (1) past or current use of an aldosterone antagonist, or (2) a medication possession ratio (adherence) <80% for any antihypertensive drug. Hyperaldosteronism was classified as an aldosterone/renin ratio (ARR) ≥30. Using the computer, 746 patients were identified who met criteria. After manual chart review to verify inclusion and exclusion criteria, 333 patients remained. Of 184 individuals in whom an ARR was obtained, 39 (21.2%) had a ratio of ≥30. A computer database is useful to identify patients with resistant hypertension and those who may have primary aldosteronism.     

A randomized trial comparing compression,perclose proglide™ and Angio‐Seal VIP™ for arterial closure following percutaneous coronary intervention: The cap trial

Objective: This prospective randomized trial compared the Angio‐Seal VIP? with Perclose Proglide? and to manual compression with respect to time to hemostasis and ambulation, patient satisfaction, and vascular complications following percutaneous coronary intervention (PCI). Background: The use of arterial closure devices for the reduction of vascular complications following PCI remains controversial. There have been no head to head trials comparing these most commonly used arterial closure devices following PCI. Methods: Two hundred patients undergoing PCI were randomized to manual compression, Perclose Proglide? or Angio‐Seal VIP?. Ambulation was allowed 3 hr after Perclose Proglide? or Angio‐Seal VIP? and 6 hr after compression. Results: There were 10 failures to deploy Perclose Proglide? and none for Angio‐Seal? (P < 0.01). Time to hemostasis was significantly shorter with Angio‐Seal VIP? compared with Perclose Proglide? (5.3 vs. 46.8 min, P < 0.01). Time to ambulation was shorter with Angio‐Seal VIP? than with Perclose Proglide? (261 vs. 334 min, P < 0.05) and the time to ambulation, as expected, was longest with compression (943 min, P < 0.01 vs. Angio‐Seal VIP? and Perclose Proglide?). Delay in ambulation was higher with Perclose Proglide? than with Angio‐Seal VIP? (18 vs. 9, P < 0.01). There was no significant difference in major vascular complications between groups. Compared with compression, patient discomfort was significantly improved with Angio‐Seal? (1.5 vs. 2.0, P < 0.01), but not with Perclose Proglide?. Conclusion: The Angio‐Seal VIP? device has a high rate of deployment success, which is significantly better than that of Perclose Proglide?. Angio‐Seal VIP? allows for earlier hemostasis and ambulation compared with both compression and Perclose Proglide? and is associated with greater patient satisfaction compared with compression. © 2008 Wiley‐Liss, Inc.     

Central markers of body fat distribution are important predictors of plasma lipids in elderly men and women

We determined the contribution of body fat distribution, peak VO₂, fat mass, and dietary intake to variation in plasma lipids in elderly individuals. Volunteers were a healthy cohort of older Caucasian women (n = 75, mean age ± SD, 72 ± 5 years) and older men (n = 101, 72 ± 5 years). We determined fat mass from underwater weighing, fat patterning from waist circumference, as well as peripheral and truncal skinfolds, exercise capacity from peak VO₂, and dietary intake from three-day food diaries. Plasma lipid levels were measured in the fasting state and included total cholesterol, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), and fasting triglycerides. Older women weighed less than older men, but had higher fat mass, truncal, and peripheral skinfolds. Waist circumference and peak VO₂ were lower in older women than older men. Older women had higher total cholesterol (217 ± 31 vs. 197 ± 30; p < 0.01), HDL-C (54 ± 12 vs. 49 ± 14; p < 0.05), and LDL-C (133 ± 26 vs. 121 ± 27; p < 0.01) when compared with older men. No gender differences were noted in fasting triglycerides. Truncal skinfolds were the best predictor of plasma lipids in older men, accounting for between 9% and 30% (r(²) of the variation in plasma lipids. Similarly, in older women, central markers of fatness (i.e., waist circumference and truncal skinfolds) were the best predictors of plasma lipids (r² = 3% to 24%). Total fat mass, peak VO₂ and dietary intake were not independent predictors of plasma lipids in older men and women. Indices of central body fatness, rather than total fat mass, peak VO₂ or dietary intake are stronger predictors of plasma lipids in healthy older men and women.     

The platelet function defect of cardiopulmonary bypass [see comments]

The use of cardiopulmonary bypass (CPB) during cardiac surgery is associated with a hemostatic defect, the hallmark of which is a markedly prolonged bleeding time. However, the nature of the putative platelet function defect is controversial. In this study, blood was analyzed at 10 time points before, during, and after CPB. We used a whole-blood flow cytometric assay to study platelet surface glycoproteins in (1) peripheral blood, (2) peripheral blood activated in vitro by either phorbol myristate acetate, the thromboxane (TX)A2 analog U46619, or a combination of adenosine diphosphate and epinephrine, and (3) the blood emerging from a bleeding-time wound (shed blood). Activation-dependent changes were detected by monoclonal antibodies directed against the glycoprotein (GP)Ib-IX and GPIIb-IIIa complexes and P-selectin. In addition, we measured plasma glycocalicin (a proteolytic fragment of GPIb) and shed-blood TXB2 (a stable breakdown product of TXA2). In shed blood emerging from a bleeding-time wound, the usual time-dependent increase in platelet surface P-selectin was absent during CPB, but returned to normal within 2 hours. This abnormality paralleled both the CPB-induced prolongation of the bleeding time and a CPB-induced marked reduction in shed-blood TXB2 generation. In contrast, there was no loss of platelet reactivity to in vitro agonists during or after CPB. In peripheral blood, platelet surface P-selectin was negligible at every time point, demonstrating that CPB resulted in a minimal number of circulating degranulated platelets. CPB did not change the platelet surface expression of GPIb in peripheral blood, as determined by the platelet binding of a panel of monoclonal antibodies, ristocetin-induced binding of von Willebrand factor, and a lack of increase in plasma glycocalicin. CPB did not change the platelet surface expression of the GPIIb-IIIa complex in peripheral blood, as determined by the platelet binding of fibrinogen and a panel of monoclonal antibodies. In summary, CPB resulted in (1) markedly deficient platelet reactivity in response to an in vivo wound, (2) normal platelet reactivity in vitro, (3) no loss of the platelet surface GPIb-IX and GPIIb-IIIa complexes, and (4) a minimal number of circulating degranulated platelets. These data suggest that the "platelet function defect" of CPB is not a defect intrinsic to the platelet, but is an extrinsic defect such as an in vivo lack of availability of platelet agonists. The near universal use of heparin during CPB is likely to contribute substantially to this defect via its inhibition of thrombin, the preeminent platelet activator.     

Extended-cycle elutriation to adjust T-cell content in HLA-disparate bone marrow transplantation

We report the development of a double-cycle elutriation (DCE) technique separating 3 or greater logs of T cells from a stem-cell-enriched marrow fraction and the results of phase I T-cell depletion studies with HLA-disparate related bone marrow transplantation (BMT) donors in two patient groups. In group 1, 10 patients with refractory hematopoietic malignancies received combination chemotherapy, total body irradiation (TBI), and immunosuppression (pre- and post-BMT), and hematopoietic rescue with a marrow transplant, depleted of T cells by elutriation. Potentially to promote engraftment and a graft-versus- leukemia (GVL) effect, 0.5 to 0.75 x 10(5) T cells/kg were added back. All 10 patients engrafted. Five patients developed acute graft-versus- host disease (GVHD; four grade II, one grade III) and two subsequently developed chronic GVHD. Two patients have relapsed (median follow-up, 206 days; range, 46 to 1,035). Four patients died of BMT-related complications (three of infection, one of veno-occlusive disease [VOD]). Four patient are disease-free survivors (median follow-up, 960 days; range, 670 to 1,035). Group 2 included five infants, four with congenital lymphohematopoietic deficiencies and one with refractory acute lymphocytic leukemia (ALL). In these infants, busulfan and increased cyclophosphamide were substituted for TBI. Only the ALL patient received added T cells. Three patients engrafted: one has stable mixed chimerism, one relapsed with ALL, and one rejected the marrow. One patient had primary autologous recovery, while another failed to engraft. None developed GVHD. We conclude that, in this setting of HLA-disparate BMT with post-BMT antithymocyte globulin (ATG) and corticosteroids, DCE significantly depletes T cells from the marrow and that a defined number of T cells can be added without the occurrence of severe GVHD.     

The role of cardiac rehabilitation in patients with heart disease

Cardiac rehabilitation is a valuable treatment for patients with a broad spectrum of cardiac disease. Current guidelines support its use in patients after acute coronary syndrome, coronary artery bypass grafting, coronary stent placement, valve surgery, and stable chronic systolic heart failure. Its use in these conditions is supported by a robust body of research demonstrating improved clinical outcomes. Despite this evidence, cardiac rehabilitation referral and attendance remains low and interventions to increase its use need to be developed.     

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women

OBJECTIVE: We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. RESEARCH DESIGN AND METHODS: We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 +/- 4 years, n = 88; group 2, 46 +/- 2 years, n = 38; group 3, 53 +/- 2 years, n = 31; and group 4. 67 +/- 6 years, n = 21. RESULTS: Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, age-related changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on age-related changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS: We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue.     

Granulocyte colony-stimulating factor for poor graft function after allogeneic stem cell transplantation: 3 days of G-CSF identifies long-term responders

Poor graft function (PGF) is a frequent cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To study the value of granulocyte colony-stimulating factor (G-CSF) in PGF, we retrospectively analyzed 81 episodes of PGF in 66 patients transplanted from 01/94 to 01/99 from an HLA-identical sibling (n = 45) or an unrelated (n = 21) donor. Median age was 29 years, 55 patients had malignancies. A total of 11 patients received a CD34+ selected graft. Viral infections (25%), myelotoxic drug (33%), fungal/bacterial infections (14%), and GVHD (31%) were present before PGF diagnosis. Median time from allo-HSCT to PGF was 75 (25-474) days. All patients were treated with G-CSF. In 77/81 episodes, there was a response that was sustained in 57. A total of 27 patients presented an increase of white cell count (WBC) >0.1 x 10(9)/l after 3 days of G-CSF. The 5-year survival was 37% and was significantly better in patients with increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (65 vs 18%, P < 0.0001). In multivariate analysis, increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (P = 0.002) was associated with better survival, while BuCy-based conditioning (P = 0.02) and GVHD (P = 0.005) were associated with higher risk of death. In conclusion, hematological response after 3 days with G-CSF predicted a better survival for patients with PGF after allo-SCT.     

Effector Cell Sensitivity to Sugar Moieties. I. Inhibition of Human Natural Killer Cell Activity by Monosaccharides

Human natural killer (NK) cells recognize multiple target antigens. The ligands (antigens) involved in the effector-target cell interaction have not been extensively identified. In the present study, assays of NK activity in the presence of a panel of monosaccharides demonstrated inhibition of cytolysis in a dose-response fashion. We propose that NK cell activity involves the recognition of carbohydrate structures on target cells via receptors on the effector cell surface.