Impact of surgical aortic valve replacement on global and regional longitudinal strain across four flow gradient patterns of severe aortic stenosis

The International Journal of Cardiovascular Imaging - To evaluate the impact of surgical aortic valve replacement (SAVR) on global (GLS) and regional longitudinal strain (RLS) across four...     

New Insights into Combinational Drug Therapy to Manage Congestion in Heart Failure

Congestion is the most important contributor to morbidity and mortality in heart failure. In patients without congestion, maintaining a neutral sodium balance is imperative to prevent evolving volume overload. Adequate use of neurohumoral blockers, in combination with dietary sodium restriction, is essential and may preclude the need for maintenance diuretic therapy. If volume overload still prevails, loop diuretics remain the mainstay treatment to reduce excessive extracellular volume. However, combinational drug therapy might offer a more attractive alternative to achieve a balanced natriuresis, instead of further uptitration of loop diuretics. Importantly, elevated cardiac filling pressures may be caused by volume misdistribution and impaired venous capacitance, rather than absolute volume overload. Vasodilator therapy to unload the heart, increase venous capacitance, and lower arterial impedance might be interesting in such cases. This review offers a practical approach into current and potential future pharmacologic therapies for managing congestion, focusing on combinational and targeted therapy.     

An animal model for human cellular immunotherapy: specific eradication of human acute lymphoblastic leukemia by cytotoxic T lymphocytes in NOD/scid mice

Adoptive immunotherapy using in vitro-generated donor-derived cytotoxic T lymphocytes (CTLs) can be effective in the treatment of relapsed leukemia after allogeneic transplantation. To determine effector cell characteristics that result in optimal in vivo antileukemic efficacy, we developed an animal model for human CTL therapy. Nonobese diabetic/severe combined immunodeficiency (NOD/scid) mice were inoculated with either of 2 primary human acute lymphoblastic leukemia (ALL), denoted as SK and OF. Anti-SK and anti-OF CTLs were generated in vitro by repeated stimulation of donor peripheral blood mononuclear cells with either SK or OF cells. Both CTL lines displayed HLA-restricted reactivity against the original targets and non-major histocompatibility class (MHC)-restricted cross-reactivity in vitro. The CTLs were administered intravenously weekly for 3 consecutive weeks to mice engrafted with either SK or OF leukemia. In 3 of 8 SK-engrafted and anti-SK-treated mice, complete remissions were achieved in blood, spleen, and bone marrow. In the remaining 5 animals partial remissions were observed. In 4 of 4 OF-engrafted anti-OF-treated mice partial remissions were observed. The antileukemic effect of specific CTLs was exerted immediately after administration and correlated with the degree of HLA disparity of the donor-patient combination. In cross-combination-treated animals, no effect on leukemic progression was observed indicating that in vivo antileukemic reactivity is mediated by MHC-restricted effector cells. The CTLs, however, displayed an impaired in vivo proliferative capacity. Ex vivo analysis showed decreased reactivity as compared to the moment of infusion. We therefore conclude that the model can be used to explore the requirements for optimal in vivo efficacy of in vitro- generated CTLs.     

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPA-filtered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.     

Hypercholesterolemia in pregnant mice does not affect atherosclerosis in adult offspring

In humans, maternal hypercholesterolemia during pregnancy promotes microscopical fatty streaks in the children. The mechanism is unknown. Fatty streaks are clinically silent, and many of them regress and never develop into advanced atherosclerosis. The aim of this study was to investigate whether hypercholesterolemia in pregnant mice induced more advanced atherosclerosis in their adult progeny. Hypercholesterolemic (HC) apolipoprotein E knockout (apoE(-/-)) female mice were mated with normocholesterolemic (NC) wild-type (apoE(+/+)) males and vice versa. All parents were almost identical genetically except for apoE. Therefore, all progeny became genetically identical and heterozygous apoE(+/-). They were born of either HC (i.e. apoE(-/-)) or NC (i.e. apoE(+/+)) mothers. The progeny were killed 6 months after birth and the amount of atherosclerosis in the aortic root was assessed. Females developed more atherosclerosis than males (P<0.001) but, regardless of sex, maternal hypercholesterolemia during pregnancy had no influence on the amount of atherosclerosis in adult progeny. Males of HC mothers had lower plasma cholesterol levels than males of NC mothers. Thus, in mice, maternal hypercholesterolemia during pregnancy does not promote the development of advanced atherosclerosis in their adult progeny.     

New CFSE-based assay to determine susceptibility to lysis by cytotoxic T cells of leukemic precursor cells within a heterogeneous target cell population

For the clinical evaluation of the efficacy of cellular immunotherapy it is necessary to analyze the effector functions of T cells against primary leukemic target cell populations which are usually considerably heterogeneous caused by differential maturation stages of the leukemic cells. An appropriate assay should not only allow the quantitative analysis of rapid cell death induction as measured by the conventional 51Cr release assay but also of the more slowly executing pathways of T-cell-induced apoptosis occurring within days instead of hours which cannot be measured using this method. Furthermore, it should dissect the differential susceptibility to T-cell-induced cell death of various target cell subpopulations and characterize the malignant precursor cells capable of producing malignant progeny. To fulfill these requirements we developed a new assay based on carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling of the target cell population combined with antibody staining of specific cell populations and addition of fluorescent microbeads to quantitatively monitor target cell death occurring within a longer time frame up to at least 5 days. This new assay facilitates the analysis of differential recognition of distinct cell types within a heterogeneous target cell population and allows simultaneously evaluation of the proliferative status of surviving target cells in response to relevant cytokines.     

Carvedilol does not alter the insulin sensitivity in patients with congestive heart failure

BACKGROUND: Congestive heart failure (CHF) has previously been shown to be associated with insulin resistance and hyperinsulinemia. A beneficial effect of the non-selective beta-blocker carvedilol has been demonstrated in patients with CHF. However, whether the drug affects the insulin sensitivity (S(i)) is unknown. AIMS: To investigate whether treatment with carvedilol alters the S(i) in patients with CHF during a prospective, double-blinded, placebo-controlled study. METHODS AND RESULTS: The patients were randomized to receive either carvedilol (n=29) or matched placebo (n=17). Insulin and glucose responses were measured during a 0.3 g/kg intravenous glucose tolerance test, and S(i) was calculated according to Bergman's Minimal Model. Baseline S(i) values correlated significantly with body mass index (r=-0.42, P=0.002), plasma urate (r=-0.42, P=0.002), plasma HDL-cholesterol (r=0.39, P=0.003), maximal oxygen uptake (r=0.35, P=0.009), plasma triglycerides (r=-0.34, P=0.01) and weight (r=-0.29, P=0.03). During the study the insulin sensitivity was unchanged in the carvedilol group compared with placebo (2.63+/-1.45 to 2.38+/-1.64 vs. 2.81+/-2.36 to 2.48+/-1.84x10(-4) min(-1)/mUl(-1), P=0.83). CONCLUSION: Additional treatment with carvedilol is neutral with regard to influence the insulin sensitivity in patients with mild to moderate CHF.