Effect of pimobendan in patients with chronic heart failure

OBJECTIVE:

To assess the effects of a calcium sensitizer, pimobendan, in patients with mild to moderate chronic heart failure.

PATIENTS AND METHODS:

Pimobendan was administered at a dose of 2.5 mg/day for 12 months to 34 patients with chronic heart failure (New York Heart Association functional class IIm to III) after treatment with diuretics and angiotensin-converting enzyme inhibitors. The etiologies of heart failure were dilated cardiomyopathy (DCM), old myocardial infarction (OMI) and other heart disease (Others). The effects of pimobendan were assessed by echocardiography, blood pool scintigraphy, Holter monitoring, ¹²³I-meta-iodobenzylguanidine (MIBG) imaging and ¹²³I-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) imaging.

RESULTS:

Pimobendan produced improvement of symptoms in the majority of patients. Improvement was more common in the DCM group than in the OMI group. Left ventricular internal diameter measured by echocardiography was significantly decreased. Left ventricular ejection fraction was significantly increased in the DCM and Others groups. The heart to mediastinum ratio on MIBG imaging was significantly increased in the DCM and Others groups, and the heart to mediastinum ratio on BMIPP imaging was significantly increased in the DCM group.

CONCLUSIONS:

Pimobendan is effective in patients with chronic heart failure but is less effective in patients with OMI than in patients with DCM or other heart diseases.     

Correlation between growth differentiation factor-15 and collagen metabolism indicators in patients with myocardial infarction and heart failure

Background Growth differentiation factor (GDF)-15, a divergent member of the transforming growth factor beta super-family does appear to be up-regulated in response to experimental pressure overload and progression of heart failure (HF). HF frequently develops after myocardial infarction (MI), contributing to worse outcome. The aim of this study is to assess the correlation between GDF-15 levels and markers related to collagen turnover in different stages of HF. Methods The study consists of a cohort of 179 patients, including stable angina pectoris patients (AP group, n = 50), old MI patients without HF (OMI group, n = 56), old MI patients with HF (OMI-HF group, n = 38) and normal Control group (n = 35). Both indicators reflecting the synthesis and degradation rates of collagen including precollagen I N-terminal peptide (PINP), type I collagen carboxy-terminal peptide (ICTP), precollagen III N-terminal peptide (PIIINP) and GDF-15 were measured using an enzyme-linked inmunosorbent assay. Results The plasma GDF-15 level was higher in OMI-HF group (1373.4 ± 275.4 ng/L) than OMI group (1036.1 ± 248.6 ng/L), AP group (784.6 ± 222.4 ng/L) and Control group (483.8 ± 186.4 ng/L) (P < 0.001). The indicators of collagen turnover (ICTP, PINP, PIIINP) all increased in the OMI-HF group compared with Control group (3.03 ± 1.02 μg/L vs. 2.08 ± 0.95 μg/L, 22.2 ± 6.6 μg/L vs. 16.7 ± 5.1 μg/L and 13.2 ± 7.9 μg/L vs. 6.4 ± 2.1 μg/L, respectively; P < 0.01). GDF-15 positively correlated with ICTP and PIIINP (r = 0.302, P < 0.001 and r = 0.206, P = 0.006, respectively). GDF-15 positively correlated to the echocardiographic diastolic indicators E/Em and left atrial pressure (r = 0.349 and r = 0.358, respectively; P < 0.01), and inversely correlated to the systolic indicators left ventricular ejection fraction and the average of peak systolic myocardial velocities (Sm) (r = -0.623 and r = -0.365, respectively; P < 0.01). Conclusion Plasma GDF-15 is associated with the indicators of type I and III collagen turnover.     

Association of Indoxyl Sulfate with Heart Failure among Patients on Hemodialysis

Background and objectives

Indoxyl sulfate, a protein-bound uremic toxin, may be associated with cardiovascular events and mortality in patients with CKD. This study aimed to investigate the relationship between indoxyl sulfate and heart failure in patients on hemodialysis.

Design, setting, participants, & measurements

Patients on hemodialysis for >6 months were enrolled within 6 months. Patients with congestive heart failure, angina pectoris, acute myocardial infarction, cerebral infarction, or cerebral hemorrhage within 3 months before the study or those <18 years old were excluded. The primary end point was first heart failure event during follow-up.

Results

In total, 258 patients (145 men) with a mean age of 57.0±14.6 years old were enrolled. Median plasma indoxyl sulfate level was used to categorize patients into two groups: the low-indoxyl sulfate group (indoxyl sulfate ≤32.35 μg/ml) and the high-indoxyl sulfate group (indoxyl sulfate >32.35 μg/ml). Then, patients were prospectively followed up for a median of 48.0 (interquartile range: 33.5–48.0) months. During follow-up, 68 patients experienced episodes of first heart failure. Kaplan–Meier analysis revealed the incidence of first heart failure event in the high–indoxyl sulfate group was significantly higher than in the low-indoxyl sulfate group (log rank P<0.001). Cox regression analysis showed indoxyl sulfate was significantly associated with first heart failure event (indoxyl sulfate as the continuous variable: hazard ratio, 1.02; 95% confidence interval [95% CI], 1.01 to 1.03; P=0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 3.49; 95% CI, 1.97 to 6.20; P<0.001). After adjustment for other confounding factors, the results remained significant (indoxyl sulfate as the continuous variable: hazard ratio, 1.04; 95% CI, 1.02 to 1.06; P<0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 5.31; 95% CI, 2.43 to 11.58; P<0.001).

Conclusions

Plasma indoxyl sulfate was associated with first heart failure event in patients on hemodialysis. Whether indoxyl sulfate is only a biomarker or involved in the pathogenesis of heart failure in hemodialysis warrants additional study.     

Consultation with cardiologists for persons with new-onset chronic heart failure: A population-based study

BACKGROUND:

It is recommended that persons recently diagnosed with heart failure consult with a specialist in heart failure.

OBJECTIVES:

To determine whether patients who were diagnosed with new-onset chronic heart failure (CHF) by a noncardiologist consulted with a cardiologist, and identify the factors associated with delayed consultation.

METHODS:

Physician reimbursement administrative data were obtained for all adults with suspected new-onset CHF in the year 2000 in Quebec, defined operationally as a physician visit for CHF (based on the International Classification of Diseases, 9th Revision diagnostic codes), with no previous physician visit code for CHF in the preceding three years. Among those first diagnosed by a noncardiologist, Cox regression modelling was used to identify patient and physician characteristics associated with time to cardiology consultation.

RESULTS:

Of the 13,523 persons coded as having incident CHF, 54.9% consulted a cardiologist within the next 2.5 to 3.5 years, and 67.4% were seen by an internist or cardiologist. Older patients, women, and those with lower comorbidity and socioeconomic status had significantly longer times to cardiology consultation.

CONCLUSION:

The data suggest that many patients with suspected new-onset CHF do not receive prompt cardiology care, as stipulated by current recommendations. Equity of access for women and those with lower socioeconomic status appears to be problematic.     

Increased morbidity in diabetic cardiac transplant recipients

BACKGROUND:

Diabetes currently affects more than 7% of the Canadian population, and heart failure is a well-documented complication of diabetes. The medical management of heart failure is often limited by disease progression, and cardiac transplantation is a key therapeutic option in end-stage disease. However, both American and Canadian guidelines continue to list diabetes as a relative contraindication to cardiac transplantation.

OBJECTIVE:

To determine the effect of preoperative diabetes on morbidity and mortality in patients undergoing cardiac transplantation.

METHODS:

A retrospective analysis of 136 adult patients undergoing cardiac transplantation at the London Health Sciences Centre (London, Ontario) between February 1995 and November 2003 was performed. Preoperatively, 14% of patients were diabetic. Unpaired Student’s t tests and χ² tests were used to compare outcomes between diabetic and nondiabetic cardiac transplant recipients.

RESULTS:

Diabetic and nondiabetic cardiac transplant recipients were similar in age, sex, body mass index and ischemic time. Preoperatively, diabetic recipients had a higher mean serum glucose and an increased incidence of ischemic cardiomyopathy. At three years postcardiac transplantation, diabetic recipients were found to have increased rates of transplant coronary artery disease, as well as decreased cardiac function. However, diabetic and nondiabetic patients showed no differences in rates of clinically significant infection or rejection in the first three postoperative months. Furthermore, survival rates were similar between these two groups.

CONCLUSION:

Diabetes is not a contraindication to cardiac transplantation, but increased vigilance is warranted in this population to minimize postoperative morbidity.     

Protective effect of Terminalia chebula against lysosomal enzyme alterations in isoproterenol-induced cardiac damage in rats

BACKGROUND:

Terminalia chebula is an ayurvedic drug recommended for the treatment of heart diseases. Earlier studies by the authors validated the beneficial cardioprotective effect of T chebula against isoproterenol-induced myocardial infarction.

OBJECTIVES:

To evaluate the therapeutic efficacy of T chebula in protecting against isoproterenol-induced lysosomal membrane damage.

METHODS:

Lysosomal enzyme activities from the serum, heart and lysosomal fractions were determined. The triphenyltetrazolium chloride assay was used to confirm the protective effect of T chebula on the myocardium.

RESULTS:

Isoproterenol administration produced significant cardiac damage (as seen by the triphenyltetrazolium chloride assay) and significantly altered lysosomal enzyme activities. Pretreatment with an ethanol extract of T chebula was found to retain near normal activities of lysosomal enzymes in rats given T chebula or T chebula plus isoproterenol compared with rats given isoproterenol alone.

CONCLUSIONS:

Pretreatment with T chebula extract stabilizes the lysosomal membrane and, thus, may have prevented myocardial damage.     

Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Objective We performed experiments using Neuregulin-1β (NRG-1β) treatment to determine a mechanism for the protective role derived from its beneficial effects by remodeling gap junctions (GJs) during heart failure (HF). Methods Rat models of HF were established by aortocaval fistula. Forty-eight rats were divided randomly into the HF (HF, n = 16), NRG-1β treatment (NRG, n = 16), and sham operation (S, n = 16) group. The rats in the NRG group were administered NRG-1β (10 μg/kg per day) for 7 days via the tail vein, whereas the other groups were injected with the same doses of saline. Twelve weeks after operation, Connexin 43 (Cx43) expression in single myocytes obtained from the left ventricle was determined by immunocytochemistry. Total protein was extracted from frozen left ventricular tissues for immunoblotting assay, and the ultrastructure of myocytes was observed by transmission electron microscopy. Results Compared with the HF group, the cardiac function of rats in the NRG group was markedly improved, irregular distribution and deceased Cx43 expression were relieved. The ultrastructure of myocytes was seriously damaged in HF rats, and NRG-1β reduced these pathological damages. Conclusions Short-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced HF, which is related to the recovery of GJs structure and the improvement of Cx43 expression.     

Serum uric acid as an index of impaired renal function in congestive heart failure

Background

Hyperuricemia is frequently present in patients with heart failure. Many pathological conditions, such as tissue ischemia, renal function impairment, cardiac function impairment, metabolic syndrome, and inflammatory status, may impact uric acid (UA) metabolism. This study was to assess their potential relations to UA metabolism in heart failure.

Methods

We retrospectively assessed clinical characteristics, echocardiological, renal, metabolic and inflammatory variables selected on the basis of previous evidence of their involvement in cardiovascular diseases and UA metabolism in a large cohort of randomly selected adults with congestive heart failure (n = 553). By clustering of indices, those variables were explored using factor analysis.

Results

In factor analysis, serum uric acid (SUA) formed part of a principal cluster of renal functional variables which included serum creatinine (SCr) and blood urea nitrogen (BUN). Univariate correlation coefficients between variables of patients with congestive heart failure showed that the strongest correlations for SUA were with BUN (r = 0.48, P < 0.001) and SCr (r = 0.47, P < 0.001).

Conclusions

There was an inverse relationship between SUA levels and measures of renal function in patients with congestive heart failure. The strong correlation between SUA and SCr and BUN levels suggests that elevated SUA concentrations reflect an impairment of renal function in heart failure.     

Correlation between epidermal growth factor receptor mutations and nuclear expression of female hormone receptors in non-small cell lung cancer: a meta-analysis

Background

Compared with male, female non-small cell lung cancer (NSCLC) patients have better response when treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), suggesting a potential association between female hormones and EGFR mutation. However, the results provided by previous studies were inconclusive and controversial. We sought to examine the link between the expression of nuclear female hormone receptors and EGFR mutations in NSCLC.

Methods

Electronic databases were used to search the relevant articles. The involved hormone receptors included estrogen receptor (ER) and progesterone receptor (PR). The primary endpoint was the occurrence of ER/PR expression and EGFR mutation in NSCLC patients.

Results

Five studies fulfilled the criteria and were included in our analysis. Patients with high ER-β expression had higher positive EGFR mutation than low ER-β patients (44.2% vs. 23.7%), and there was a significant difference between the two groups [odds radio (OR) 3.44, 95% confidence interval (CI): 2.40-4.93, Z=6.72, P<0.001]. However, there is no significant correlation between EGFR mutations and ER-α (when included ER-α3, OR 1.20, 95% CI: 0.62-2.33, Z=0.55, P=0.58; and when included ER-α4, OR 1.18, 95% CI: 0.62-2.25, Z=0.51, P=0.61) or PR (OR 1.29, 95% CI: 0.40-4.10, Z=0.43, P=0.67). No significant publication bias was observed.

Conclusions

High nuclear expression of ER-β, but not ER-α or PR is correlated with EGFR mutations in NSCLC. The underlying mechanism and potential translational relevance warrant further investigation.     

The Future as a Series of Transitions: Qualitative Study of Heart Failure Patients and Their Informal Caregivers

BACKGROUND

Advance care planning often only focuses on written advance directives rather than on future goals important to patients and families. Heart failure has a particularly uncertain future with variable clinical trajectories. A better understanding of patient and family concerns about and perceptions of the future could improve advance care planning.

OBJECTIVE

We aimed to identify how patients with heart failure and their informal (family) caregivers perceive their future.

DESIGN

This was a cross-sectional study using qualitative methods.

PARTICIPANTS

Thirty-three patients from an academic health care system with New York Heart Association class II–IV heart failure and 20 of their informal caregivers participated in the study. We used a purposive sampling strategy to include patients within a range of ages and health statuses.

APPROACH

Participants were asked in individual, semi-structured interviews: “When you think about what lies ahead, what comes to mind?” Qualitative analysis used an inductive approach. Early in the analysis, it became clear that participants’ narratives about the future were described in terms of past transitions. This led us to use transition theory to further guide analysis. Transition theory describes how people restructure their reality and resolve uncertainty during change.

KEY RESULTS

Patients and their caregivers talked about past and present transitions when asked about the future: “The present gets in the way of talking about the future.” We identified four common pivotal transitions, including the shock of first being diagnosed with heart failure; learning to adjust to life with heart failure; reframing and taking back control of one’s life; and understanding and accepting that death is inevitable. Concerns about the future were framed based on the most recent transition.

CONCLUSIONS

Heart failure is a series of transitions according to patients and caregivers. By recognizing and educating patients about transitions, identifying transition-specific concerns, and supporting patients and caregivers through transitions, the process of planning for the future as part of advance care planning may be improved.KEY WORDS: advance care planning, transitions, palliative care, decision making, patient-centered care     

Role of tumour necrosis factor-alpha and other cytokines in ischemia-reperfusion-induced injury in the heart

BACKGROUND:

Several investigations have implicated cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-6, IL-8 and transforming growth factor-beta in the pathophysiology of cellular dysfunction in ischemia-reperfusion (I/R). Although an increase in the production of these cytokines has been detected after myocardial infarction and cardiopulmonary bypass surgery, their exact role and mechanisms for inducing cardiac dysfunction are poorly understood.

OBSERVATIONS:

TNF-α, transforming growth factor-beta, IL-1, IL-6 and IL-8 have frequently been studied in different cardiovascular diseases, including I/R injury in the heart. Low concentrations of TNF-α appear to exert cardioprotective effects, whereas high concentrations have been shown to produce deleterious actions in the heart. Some efforts have been made to explore the molecular mechanisms of cytokine actions; however, such information is insufficient to develop therapeutic strategies to combat their deleterious effects during the development of I/R injury in the heart.

CONCLUSIONS:

In addition to a time-dependent response, the conflicting effects of cytokines seem to depend on their concentrations used in different experimental studies. It is also likely that both the beneficial and pathophysiological actions of cytokines occur concomitantly. On the basis of the existing literature, it is suggested that different ways need to be found to modify the synthesis as well as the cardiodepressant actions of cytokines to improve the therapy of ischemic heart disease.     

Interaction of staphylococcal toxic shock syndrome toxin-1 and enterotoxin A on T cell proliferation and TNF�� secretion in human blood mononuclear cells

BACKGROUND:

The majority of menstrual toxic shock syndrome (MTSS) cases are caused by a single clone of Staphylococcus aureus that produces both toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA).

OBJECTIVE:

To determine whether the two superantigens interact to cause an enhancement of biological activity in human peripheral blood mononuclear cells (PBMCs).

DESIGN:

PBMCs from nine healthy donors were stimulated with TSST-1 or SEA, either alone or in combination at their minimum effective concentrations.

SETTING:

In vitro study.

INTERVENTIONS:

Human PBMCs were stimulated in vitro with TSST-1 (1 pg/mL), SEA (0.1 pg/mL) or combination for 20 to 72 h. Mitogenic response was determined by [³H]-thymidine incorporation. PBMC culture supernatants were assayed for the presence of tumour necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6 by ELISA.

MAIN RESULTS:

The combination of TSST-1 and SEA induced significantly greater mitogenesis in human PBMCs compared with either toxin alone (P<0.05, paired Student’s t test, two-tailed). Similarly, the production of TNFα in culture supernatants was significantly greater in the combination of TSST-1 and SEA compared with either TSST-1 or SEA alone (P<0.05). In contrast, no enhancement in the levels IL-1 or IL-6 was observed.

CONCLUSIONS:

These data suggest that the co-production of TSST-1 and SEA by S aureus may provide some biological advantage to the organism throughs an enhanced effect of these superantigens on T cell activation and TNF secretion.     

Administrative data have high variation in validity for recording heart failure

BACKGROUND:

Many studies have relied on administrative data to identify patients with heart failure (HF).

OBJECTIVE:

To systematically review studies that assessed the validity of administrative data for recording HF.

METHODS:

English peer-reviewed articles (1990 to 2008) validating International Classification of Diseases (ICD)-8, -9 and -10 codes from administrative data were included. An expert panel determined which ICD codes should be included to define HF. Frequencies of ICD codes for HF were calculated using up to the 16 diagnostic coding fields available in the Canadian hospital discharge abstract during fiscal years 2000/2001 and 2005/2006.

RESULTS:

Between 1992 and 2008, more than 70 different ICD codes for defining HF were used in 25 published studies. Twenty-one studies validated hospital discharge abstract data; three studies validated physician claims and two studies validated ambulatory care data. Eighteen studies reported sensitivity (range 29% to 89%). Specificity and negative predictive value were greater than 70% across 17 studies. Nineteen studies reported positive predictive values (range 12% to 100%). Ten studies reported kappa values (range 0.39 to 0.84).For Canadian hospital discharge data, ICD-9 and -10 codes 428 and I50 identified HF in 5.50% and 4.80% of discharge records, respectively. Additional HF-related ICD-9 and -10 codes did not impact HF prevalence.

CONCLUSION:

The ICD-9 and -10 codes 428 and I50 were the most commonly used to define HF in hospital discharge data. Validity of administrative data in recording HF varied across the studies and data sources that were assessed.     

Genetic Polymorphism G894T and the Prognosis of Heart Failure Outpatients

Background

Previous studies have analyzed the role of the genetic polymorphism of endothelial nitric oxide synthase on heart failure prognosis. However, there are no studies relating the G894T and heart failure in Brazil.

Objective

To evaluate the association between G894T GP and the prognosis of a sample of Brazilian outpatients with heart failure.

Methods

Cohort study included 145 patients with systolic heart failure, followed for up to 40 months (mean = 22), at two university hospitals, in the State of Rio de Janeiro. We evaluated the relationship between G894T and the following outcomes: reverse remodeling, improvement in functional class (NYHA), and mortality and hospitalization rates. The diameters of the left atrium and ventricle, as well as the ejection fraction of the left ventricle, were evaluated at baseline and at 6 months to assess reverse remodeling. The improvement in functional class was evaluated after 6 months, and mortality rate and hospitalization were evaluated during follow-up. Race was self-declared. G894T polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism.

Results

The genotypic frequencies were GG (40%), GT (48.3%) and TT (11.7%). The allele frequency was guanine (64.1%) and thiamine (35.8%). There were no differences between the genotype or allelic frequencies according to self declared race, either as baseline characteristics. There was no relationship between genotype or allele frequency and the outcome measures.

Conclusion

No association was observed between the G894T polymorphism (Glu298Asp) and prognosis in this sample of Brazilian outpatients with systolic heart failure.     

The influence of renal insufficiency on sleep-disordered breathing in patients with symptomatic chronic heart failure

BACKGROUND:

Renal insufficiency, a common condition among patients with chronic heart failure, complicates the management of heart failure. However, the influence of renal insufficiency on sleep-disordered breathing (SDB) – another important comorbidity of heart failure – has not been well studied.

METHODS:

Seventy-nine patients (60 men and 19 women) with stable, symptomatic heart failure caused by left ventricular systolic dysfunction (left ventricular ejection fraction of less than 45%) were studied.

RESULTS:

Thirty-nine patients (49%) had SDB as defined by an apnea-hypopnea index (AHI) of five or greater: 15 patients were classified as having mild SDB (AHI of five or greater and less than 15), 10 patients as having moderate SDB (AHI of 15 or greater and less than 30) and 14 patients as having severe SDB (AHI of 30 or greater). The etiology of SDB was predominantly central. Plasma brain natriuretic peptide concentration in the severe SDB group was 587±377 pg/mL, which was significantly higher than those of the remaining three groups (P<0.05). On the other hand, estimated glomerular filtration rate (eGFR) was comparable between non-SDB and SDB groups. There was no statistically significant correlation between eGFR and AHI, or between eGFR and the number of central sleep apneas in the study patients.

CONCLUSION:

Higher plasma brain natriuretic peptide concentrations were associated with more severe SDB, whereas the level of eGFR was not correlated with the severity of SDB. The results suggest that renal dysfunction plays a relatively minor role in determining breathing abnormalities in chronic heart failure.     

Intervention to Improve Care at Life’s End in Inpatient Settings: The BEACON Trial

Background

Widespread implementation of palliative care treatment plans could reduce suffering in the last days of life by adopting best practices of traditionally home-based hospice care in inpatient settings.

Objective

To evaluate the effectiveness of a multi-modal intervention strategy to improve processes of end-of-life care in inpatient settings.

Design

Implementation trial with an intervention staggered across hospitals using a multiple-baseline, stepped wedge design.

Participants

Six Veterans Affairs Medical Centers (VAMCs).

Intervention

Staff training was targeted to all hospital providers and focused on identifying actively dying patients and implementing best practices from home-based hospice care, supported with an electronic order set and paper-based educational tools.

Main Measures

Several processes of care were identified as quality endpoints for end-of-life care (last 7 days) and abstracted from electronic medical records of veterans who died before or after intervention (n = 6,066). Primary endpoints were proportion with an order for opioid pain medication at time of death, do-not-resuscitate order, location of death, nasogastric tube, intravenous line infusing, and physical restraints. Secondary endpoints were administration of opioids, order/administration of antipsychotics, benzodiazepines, and scopolamine (for death rattle); sublingual administration; advance directives; palliative care consultations; and pastoral care services. Generalized estimating equations were conducted adjusting for longitudinal trends.

Key Results

Significant intervention effects were observed for orders for opioid pain medication (OR: 1.39), antipsychotic medications (OR: 1.98), benzodiazepines (OR: 1.39), death rattle medications (OR: 2.77), sublingual administration (OR: 4.12), nasogastric tubes (OR: 0.71), and advance directives (OR: 1.47). Intervention effects were not significant for location of death, do-not-resuscitate orders, intravenous lines, or restraints.

Conclusions

This broadly targeted intervention strategy led to modest but statistically significant changes in several processes of care, indicating its potential for widespread dissemination to improve end-of-life care for thousands of patients who die each year in inpatient settings.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-013-2724-6) contains supplementary material, which is available to authorized users.KEY WORDS: palliative care, end-of-life care, palliative medicine, hospice, inpatient     

Deferasirox is a powerful NF-��B inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging

Background

Usefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-κB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes.

Design and Methods

We evaluated deferasirox activity on nuclear factor-κB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 μM deferasirox for 18h.

Results

Nuclear factor-κB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate.

Conclusions

Nuclear factor-κB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies.     

Effects of metoprolol and amiodarone combination on heart rate,myocardial contractility and coronary flow: Study in isolated perfused rat hearts

BACKGROUND:

Beta-blockers and amiodarone have been used concomitantly to treat arrhythmias associated with congestive heart failure. However, the combination of metoprolol and amiodarone has only been studied restrospectively, and its potential effects in congestive heart failure remain to be properly elucidated in prospective trials.

OBJECTIVE:

The present investigation focused on evaluating the pharmacological interaction between metoprolol and amiodarone in an isolated perfused rat heart preparation.

MATERIALS AND METHODS:

Adult male Wistar rats (n=24) were divided into four groups of six animals, and the effects of the metoprolol/amiodarone combination on systolic pressure, myocardial contractility (dP/dt), coronary flow (CF) and heart rate were analyzed, and the interdependent variables were compared.

RESULTS:

There was a negative chronotropic effect by both metoprolol and the metoprolol/amiodarone combination in isolated rat hearts. However, the acute effects of the metoprolol/amiodarone combination showed no myocardial contractility depression or bradycardia accentuation compared with metoprolol alone. CF increased by 9.2% at minute 1 through minute 5 (P=0.004) with the metoprolol/amiodarone combination. There was no difference in systolic pressure or myocardial contractility among the groups.

CONCLUSIONS:

The acute effects of the metoprolol/amiodarone combination in the isolated rat heart were an increase in CF, and no myocardial contractility depression or bradycardia accentuation.     

LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes

Background:

Hepatitis C virus infection is one of the leading causes of end stage liver diseases. The innate immune response slows down viral replication by activating cytokines such as type I interferon (IFN-α/β), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. Recently, leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) was reported contributing to the production of interferon-β in macrophages.

Objectives:

The aim of this study was to assess the role of LRRFIP1 in induction of IFN-β and inhibition of HCV infection in hepatocytes.

Materials and Methods:

Induction of IFN-β by LRRFIP1 in Huh7 and Huh7.5.1 was determined by real-time PCR and western blotting in vitro. Inhibition of HCV replication by LRRFIP1 overexpression in hepatocytes was assessed.

Results:

LRRFIP1 increased the expression of IFN-β in hepatocytes with or without HCV infection. Induction of IFN-β by LRRFIP1 was enhanced with the presence of hepatitis C virus. Overexpression of LRRFIP1 in hepatocytes inhibited HCV replication. However, HCV infection did not regulate intracellular expression of LRRFIP1.

Conclusions:

LRRFIP1 and its mediated production of type I interferon play a role in controlling HCV infection. The findings of this study provide new target for HCV treatment and contribute to development of anti-HCV drugs.