Contractile function is preserved in unloaded hearts despite atrophic remodeling

OBJECTIVE: Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. MATERIAL AND METHODS: Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. RESULTS: Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). CONCLUSION: Atrophic remodeling involves both the myocyte and interstitial tissue compartment. These data suggest that although there is decreased myocardial volume and increased stiffness, contractile capacity is preserved in the long-term unloaded heart.

Valved stents for transapical pulmonary valve replacement

OBJECTIVES: Pulmonary valve insufficiency remains a leading cause for reoperations in congenital cardiac surgery. The current percutaneous approach is limited by the size of the access vessel and variable right ventricular outflow tract morphology. This study assesses the feasibility of transapical pulmonary valve replacement based on a new valved stent construction concept. METHODS: A new valved stent design was implanted off-pump under continuous intracardiac echocardiographic and fluoroscopic guidance into the native right ventricular outflow tract in 8 pigs (48.5 +/- 6.0 kg) through the right ventricular apex, and device function was studied by using invasive and noninvasive measures. RESULTS: Procedural success was 100% at the first attempt. Procedural time was 75 +/- 15 minutes. All devices were delivered at the target site with good acute valve function. No valved stents dislodged. No animal had significant regurgitation or paravalvular leaking on intracardiac echocardiographic analysis. All animals had a competent tricuspid valve and no signs of right ventricular dysfunction. The planimetric valve orifice was 2.85 +/- 0.32 cm(2). No damage to the pulmonary artery or structural defect of the valved stents was found at necropsy. CONCLUSIONS: This study confirms the feasibility of direct access valve replacement through the transapical procedure for replacement of the pulmonary valve, as well as validity of the new valved stent design concept. The transapical procedure is targeting a broader patient pool, including the very young and the adult patient. The device design might not be restricted to failing conduits only and could allow for implantation in a larger patient population, including those with native right ventricular outflow tract configurations.

Retaining perivascular tissue of human saphenous vein grafts protects against surgical and distension-induced damage and preserves endothelial nitric oxide synthase and nitric oxide synthase activity

OBJECTIVE: Conventional harvesting of saphenous vein used for coronary artery bypass surgery induces a vasospasm that is overcome by high-pressure distension. Saphenous vein harvested with its cushion of perivascular tissue by a "no touch" technique does not undergo vasospasm and distension is not required, leading to an improved graft patency. The aim of this study is to investigate the effect of surgical damage and high-pressure distension on endothelial integrity and endothelial nitric oxide synthase expression and activity in saphenous vein harvested with and without perivascular tissue. METHODS: Saphenous veins from patients (n = 26) undergoing coronary artery bypass surgery were prepared with and without perivascular tissue. We analyzed the effect of 300 mm Hg distension on morphology and endothelial nitric oxide synthase/nitric oxide synthase activity using a combination of immunohistochemistry, Western blot analysis, reverse transcriptase polymerase chain reaction, and enzyme assay in distended (with and without perivascular tissue) compared with nondistended (with and without perivascular tissue) segments. RESULTS: Distension induced substantial damage to the luminal endothelium (assessed by CD31 staining) and vessel wall. Endothelial nitric oxide synthase expression and activity were significantly reduced by high-pressure distension and removal of, or damage to, perivascular tissue. The effect of distension was significantly less for those with perivascular tissue than for those without perivascular tissue in most cases. CONCLUSION: The success of the saphenous vein used as a bypass graft is affected by surgical trauma and distension. Veins removed with minimal damage exhibit increased patency rates. We show that retention of perivascular tissue on saphenous vein prepared for coronary artery bypass surgery by the "no touch" technique protects against distension-induced damage, preserves vessel morphology, and maintains endothelial nitric oxide synthase/nitric oxide synthase activity.

Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade initiated by IL-5 in eosinophils

BACKGROUND: Eosinophil differentiation, activation, and survival are largely regulated by IL-5. IL-5-mediated transmembrane signal transduction involves both Lyn-mitogen-activated protein kinases and Janus kinase 2-signal transducer and activator of transcription pathways. OBJECTIVE: We sought to determine whether additional signaling molecules/pathways are critically involved in IL-5-mediated eosinophil survival. METHODS: Eosinophil survival and apoptosis were measured in the presence and absence of IL-5 and defined pharmacologic inhibitors in vitro. The specific role of the serine/threonine kinase proviral integration site for Moloney murine leukemia virus (Pim) 1 was tested by using HIV-transactivator of transcription fusion proteins containing wild-type Pim-1 or a dominant-negative form of Pim-1. The expression of Pim-1 in eosinophils was analyzed by means of immunoblotting and immunofluorescence. RESULTS: Although pharmacologic inhibition of phosphatidylinositol-3 kinase (PI3K) by LY294002, wortmannin, or the selective PI3K p110delta isoform inhibitor IC87114 was successful in each case, only LY294002 blocked increased IL-5-mediated eosinophil survival. This suggested that LY294002 inhibited another kinase that is critically involved in this process in addition to PI3K. Indeed, Pim-1 was rapidly and strongly expressed in eosinophils after IL-5 stimulation in vitro and readily detected in eosinophils under inflammatory conditions in vivo. Moreover, by using specific protein transfer, we identified Pim-1 as a critical element in IL-5-mediated antiapoptotic signaling in eosinophils. CONCLUSIONS: Pim-1, but not PI3K, plays a major role in IL-5-mediated antiapoptotic signaling in eosinophils.

Discontinuation of enfuvirtide in heavily pretreated HIV-infected individuals

BACKGROUND: Enfuvirtide was shown to be highly effective in treatment- experienced patients. Data on discontinuation of enfuvirtide and switch to new antiretroviral drugs are scarce. We aimed to evaluate the efficacy and the impact of discontinuing and/or switching enfuvirtide on virologic and clinical parameters in clinical practice. METHODS: All HIV-infected individuals participating in the Swiss HIV Cohort Study who were treated with enfuvirtide for at least 4 weeks in combination with an optimized background antiretroviral regimen were included in this study. RESULTS: A total of 151 patients were analyzed. The median baseline CD4 cell count was 108 cells/microL (interquartile range [IQR] 50-206) and HIV RNA was 4.7 log10 copies/mL (IQR 4.1-5.2). Virologic suppression, defined as a viral load below 50 copies/mL at 12 months, was achieved by 57.6% of patients. Overall, a median CD4 cell increase of 121 cells/microL (IQR 50-189) from baseline was noted. Up to 50% of patients discontinued enfuvirtide within the first year of treatment, mainly because of the patient's choice. After discontinuation of enfuvirtide, high rates of virologic failure and clinical progression were observed, notably when CD4 cell count at stopping enfuvirtide was below 100 cells/microL and no switch to new potent antiretroviral drugs such as darunavir, maraviroc, or raltegravir was performed. CONCLUSIONS: Enfuvirtide provides high virologic and immunologic response in treatment-experienced patients in the setting of clinical practice. Enfuvirtide should not be discontinued but should be replaced by new potent antiretrovirals, particularly in case of severe immunosuppression.

Comparison of phenotypes of childhood wheeze and cough in 2 independent cohorts

BACKGROUND Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). OBJECTIVE To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. METHODS We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. RESULTS When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. CONCLUSIONS Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes.